N-(Phosphonoalkyl)-Amino Acids, Derivatives Thereof and Compositions and Methods of Use

ABSTRACT

The present invention relates to an N-(phosphonoalkyl)-amino acid, a related compound or a derivative thereof, the N-(phosphonoalkyl)-amino acid, related compound or derivative thereof being in a form as a free acid, salt, partial salt, lactone, amide or ester, or in stereoisomeric or non-stereoisomeric form, other than N-(phosphonomethyl)-glycine or N,N-bis(phosphonomethyl)-glycine. Also included is a composition including an N-(phosphonoalkyl)-amino acid, a related compound or a derivative thereof in a form as a free acid, salt, partial salt, lactone, amide or ester, or in stereoisomeric or non-stereoisomeric form, and a cosmetically or pharmaceutically acceptable vehicle for topical or systemic administration to a mammalian subject, as well as a method of administering an effective amount of such a composition for alleviating or improving a condition, disorder, symptom or syndrome associated with at least one of a nervous, vascular, musculoskeletal or cutaneous system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 12/194,203, filed Aug. 19, 2008, now allowed, which is adivisional application of U.S. patent application Ser. No. 11/621,287,filed Jan. 9, 2007, now U.S. Pat. No. 7,429,575, issued Sep. 30, 2008,which claims the benefit under 35 U.S.C. § 119(e) of U.S. ProvisionalApplication No. 60/757,614, filed Jan. 10, 2006. The entire disclosuresof all of the above applications are hereby incorporated herein byreference.

BACKGROUND OF THE INVENTION

The present invention relates to an N-(phosphonoalkyl)-amino acid, arelated compound or a derivative thereof, the N-(phosphonoalkyl)-aminoacid, related compound or derivative thereof being in a form as a freeacid, salt, partial salt, lactone, amide or ester, or in stereoisomericor non-stereoisomeric form, other than N-(phosphonomethyl)-glycine orN,N-bis(phosphonomethyl)-glycine. The present invention also relates toa composition including an N-(phosphonoalkyl)-amino acid, a relatedcompound or a derivative thereof in a form as a free acid, salt, partialsalt, lactone, amide or ester, or in stereoisomeric ornon-stereoisomeric form, and a cosmetically or pharmaceuticallyacceptable vehicle for topical or systemic administration to a mammaliansubject, as well as a method of administering an effective amount ofsuch a composition for alleviating or improving a condition, disorder,symptom or syndrome associated with at least one of a nervous, vascular,musculoskeletal or cutaneous system.

N-(Phosphonomethyl)-glycine is listed as glyphosate, C₃H₈NO₅P, molecularweight 169, in The Merck Index, 13^(th) edition, 2001, page 803. Themono(isopropylamine) salt of N-(phosphonomethyl)-glycine is a primaryactive ingredient in Roundup® herbicide.N,N-Bis(phosphonomethyl)-glycine is listed as glyphosine, C₄H₁₁NO₈P₂,molecular weight 263, in The Merck Index, 13^(th) edition, 2001, page804. This compound is listed as plant growth regulator known to causechlorosis in green plants, and also used as a chemical ripener. U.S.Pat. No. 3,288,846 entitled “Processes for Preparing Organo-PhosphonicAcids” describes a synthesis of N-substituted aminomethylenephosphonicacid. U.S. Pat. No. 3,799,758 entitled “N-Phosphonomethyl-GlycinePhytotoxicant Compositions” describes N-(phosphonomethyl)-glycine andits derivatives useful as phytotoxicants and herbicides. U.S. Pat. No.3,853,530 entitled “Regulating Plants with N-phosphonomethyl-Glycine andDerivatives Thereof” describes the use of N-Phosphonomethyl-glycine andderivatives useful for regulating the natural growth and development ofplants.

There has been no teaching, suggestion or implication about the use ofN-(phosphonomethyl)-glycine or its derivatives for topical or systemicadministration to mammals, including humans. The present inventors havedetermined that such compounds are useful for treating various medicaland cosmetic conditions in animals, such as mammals, and includinghumans.

BRIEF SUMMARY OF THE INVENTION

One aspect of the present invention relates to anN-(phosphonoalkyl)-amino acid, a related compound or a derivativethereof, the N-(phosphonoalkyl)-amino acid, related compound orderivative thereof being in a form as a free acid, salt, partial salt,lactone, amide or ester, or in stereoisomeric or non-stereoisomericform, other than N-(phosphonomethyl)-glycine orN,N-bis(phosphonomethyl)-glycine.

Another aspect of the present invention relates to anN-(phosphonoalkyl)-amino acid compound, a related compound or a compoundderived therefrom, the compound includes the group consisting ofN-(phosphonoalkyl)-proline and a compound or derivative thereof havingthe following formula:

R₁CH(NR₂R₃)(CH₂)_(m)COR₄

wherein R₁ is H, an alkyl group having 1 to 19 carbon atoms, an arylgroup having 6 to 19 carbon atoms or an aralkyl group having 7 to 19carbon atoms; and R₁ can also carry —OH, —SH, —SCH₃, —NH₂, —NR₂R₃,—COR₄, —NHCONH₂, —NHC(═NR₂)NH₂, imidazole, pyrrolidine or otherheterocyclic group; m is an integer from 0 to 5; R₂ is a phosphonoalkylgroup having a formula (HO)₂PO(CH₂)_(n)—; R₃ is H or a phosphonoalkylgroup having a formula (HO)₂PO(CH₂)_(n)—; n is an integer from 1 to 9;R₄ is —NH₂ or —OR₅, R₅ is H, an alkyl group having 1 to 19 carbon atoms,an aryl group having 6 to 19 carbon atoms or an aralkyl group having 7to 19 carbon atoms; and the H attached to any carbon atom can besubstituted by I, F, Cl, Br, OH or an alkoxy group having 1 to 9 carbonatoms; and wherein the N-(phosphonoalkyl)-amino acid, related compoundor derivative thereof is in a form as a free acid, salt, partial salt,lactone, amide or ester, or in a stereoisomeric or non-stereoisomericform; provided that the compound is not N-(phosphonomethyl)-glycine orN,N-bis(phosphonomethyl)-glycine.

Another aspect of the present invention relates to a compositioncomprising an N-(phosphonoalkyl)-amino acid, a related compound or aderivative thereof, the N-(phosphonoalkyl)-amino acid, related compoundor derivative thereof being in a form as a free acid, salt, partialsalt, lactone, amide or ester, or in stereoisomeric ornon-stereoisomeric form, and a cosmetically or pharmaceuticallyacceptable vehicle for topical or systemic administration to a mammaliansubject.

Yet another aspect of the present invention relates to a method ofalleviating or improving a condition, disorder, symptom or syndromeassociated with at least one of a nervous, vascular, musculoskeletal orcutaneous system, the method comprising administering to a mammaliansubject having the disorder, symptom or syndrome an amount effective foralleviating or improving the condition, disorder, symptom or syndrome ofa composition comprising an N-(phosphonoalkyl)-amino acid, a relatedcompound or a derivative thereof, the N-(phosphonoalkyl)-amino acid,related compound or derivative thereof being in a form as a free acid,salt, partial salt, lactone, amide or ester, or in stereoisomeric ornon-stereoisomeric form, and a cosmetically or pharmaceuticallyacceptable vehicle for topical or systemic administration to themammalian subject.

The cosmetic conditions and medical disorders, symptoms or syndromesassociated with at least one of a nervous, vascular, musculoskeletal orcutaneous system, and others, include, by way of example and notlimitation, itch, pain, inflammation, erythema, eczema, dermatitis,dermatoses, arthritis, acne, rosacea, dry skin, ichthyosis, keratoses,psoriasis, pigmented skin, aging related skin changes. The compositionsmay also be used for skin lightening.

As used herein, the singular forms “a”, “an”, and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a compound” includes a plurality of suchcompounds.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention relates to anN-(phosphonoalkyl)-amino acid, a related compound or a derivativethereof, the N-(phosphonoalkyl)-amino acid, related compound orderivative thereof being in a form as a free acid, salt, partial salt,lactone, amide or ester, or in stereoisomeric or non-stereoisomericform, other than N-(phosphonomethyl)-glycine orN,N-bis(phosphonomethyl)-glycine.

Typical, but non-limiting phosphonoalkyl groups include phosphonomethyl,phosphonoethyl, phosphonopropyl, phosphonoisopropyl, phosphonobutyl,phosphonoisobutyl, phosphonopentyl, phosphonoisopentyl, phosphonooctyland phosphonoisooctyl groups.

The present invention also relates to a composition including anN-(phosphonoalkyl)-amino acid, a related compound or a derivativethereof in a form as a free acid, salt, partial salt, lactone, amide orester, or in stereoisomeric or non-stereoisomeric form, and acosmetically or pharmaceutically acceptable vehicle for topical orsystemic administration to a mammalian subject. The composition includesN-(phosphonoalkyl)-glycine, its related compounds and derivativesthereof, since they are not known for use in treating mammals, includinghumans.

The present invention additionally relates to a method of administeringan effective amount of such a composition for alleviating or improving acondition, disorder, symptom or syndrome associated with at least one ofa nervous, vascular, musculoskeletal or cutaneous system, or others.

The compositions comprising N-(phosphonoalkyl)-amino acids, preferablyN-(phosphonomethyl)-amino acids, related compounds or derivativesthereof, and their topical or systemic administration to animals, suchas mammals, including humans, are believed to be beneficial ortherapeutically effective for cosmetic conditions or medical disordersassociated with nervous, vascular, masculoskeletal, or cutaneoussystems, or others.

The amino acid as used herein represents as a broad definition anorganic compound which has at least one carboxyl group and at least onealkaline group such as amino, imino or guanidino group. The common aminoacids represent twenty amino acids which have an amino group at thealpha position of the carbon chain and are present in proteins. Thesecommon amino acids are alanine, arginine, aspartic acid, asparagine,cysteine, glycine, glutamic acid, glutamine, histidine, isoleucine,leucine, lysine, methionine, phenylalanine, proline, serine, threonine,tryptophan, tyrosine and valine. From these common amino acids, twentyN-(phosphonoalkyl)-amino acids, preferably twentyN-(phosphonomethyl)-amino acids can be formed including differentstereoisomers such as D, L and DL forms.

Some amino acids are metabolites or are related to or derived from thecommon amino acids. Other amino acids have amino group(s) at otherpositions of the carbon chain, such as the β or γ position. Still otheramino acids are found in nature produced by microorganisms or plants.Certain amino acids, such as taurine, can have a sulfonic acid groupinstead of a carboxyl group. Peptides are derived from amino acids, andthe peptides are called related amino acids or amino acid derivatives.Other organic compounds which have at least one carboxyl group and atleast one alkaline group such as amino, imino or guanidino group arealso called “related” amino acids. As used herein, all these compoundsare called related amino acids. Representative, but non-limiting relatedamino acids include: β-alanine, γ-aminobutanoic acid, β-aminoisobutanoicacid, anserine, aminolevulinic acid, carnosine, canaline, canavanine,citrulline, creatine, creatinine, cysteine sulfinic acid, cystine,cycloserine, dopa (3,4-dihydroxyphenylalanine), dopamine(hydroxytyramine), ethionine, glutathione, guanidinoacetic acid,homocarnosine, homocysteine, homoserine, 4-hydroxyphenylglycine,hydroxyglutamic acid, hydroxylysine, hydroxyproline, hypusine,homoarginine, homocitrulline, homocystine, homophenylalanine,homotryptophan, hydroxylysine, hydroxyarginine, hydroxyhomoarginine,hydroxycitrulline, hydroxyornithine, hydroxyvaline, indospicine,methoxinine, methylarginine, methylhistidine, methyllysine,methylornithine, methylserine, norvaline, ornithine, oxalysine,penicillamine(dimethylcysteine), phenylglycine, 3-phenylserine,sarcosine (N-methylglycine), serotonin (hydroxytryptamine), taurine,tryptamine and tyramine.

As used herein, the N-(phosphonoalkyl) or preferably theN-(phosphonomethyl) derivatives of the amino acids as described inparagraphs [0016] and [0017] above, and certain others describedelsewhere herein, are called “N-(phosphonoalkyl)-related amino acids,”preferably “N-(phosphonomethyl)-related amino acids,” or simply “relatedcompounds” (or other similar grammatical terms). The “derivativesthereof” (or other similar grammatical forms) represent all othercompounds which are chemically derived from the N-(phosphonoalkyl)-aminoacids, the N-(phosphonoalkyl)-related amino acids, and preferablyN-(phosphonomethyl)-amino acids and N-(phosphonomethyl)-related aminoacids.

Conditions, disorders, symptoms and syndromes associated with the (A)nervous, (B) vascular, (C) masculoskeletal, (D) cutaneous system, andothers that may be treated with a composition of the present inventioncan be described as follows.

(A) Nervous System.

Throughout this description, the conditions, disorders, symptoms andsyndromes associated with the nervous system include the followingconditions or disorders, which may present as indicated, or otherwise:(1) dementia and Alzheimer's disease: progressive loss of memory,shrinkage and atrophy of cerebral cortex, tangles of fibers in nervecells, senile plaques of amyloid, decreased choline acetyltransferaseenzyme; (2) carpal tunnel syndrome: weakness, pain, tingling, numbness,burning in palm and fingers; (3) encephalitis: inflammation of thebrain; (4) headache: migraine, expansion of blood vessels pressing onnerves or constriction blocking blood supply, inflammation, musclecontraction to face, neck or scalp; (5) meningitis: infection of spinalfluid and meninges; (6) neuralgia: nerve pain, peripheral neuropathy,sciatica, shingles, trigeminal neuralgia; (7) Parkinson's disease:tremors in limbs, muscular rigidity; (8) amnesia: loss of memory andinability to form new memory; and (9) others, such as ataxia, Bell'spalsy, epilepsy, multiple sclerosis, myasthenia gravis, narcolepsy,paralysis and rabies.

(B) Vascular System.

Throughout this description, vascular conditions, reactions anddisorders that may be treated with a composition of the presentinvention include acanthosis nigricans, acrocyanosis, actinic cheilitis,actinic prurigo, dermatitis, dermatosis, dermographism, dyshidrosis,drug eruptions, eczema, erythema, erythema migrans, erythrocyanosis,erythromelalgia, familial hemorrhage, histamine reaction, inflammatorypapular and pustular lesions, lichen planus, lupus erythematosus,mycosis fungoides, neurodermatitis, neuropeptide and neurovascularreactions, parapsoriasis, perniosis (chilblains), photoallergy,photoreaction, photosensitivity, pityriasis rosea, pityriasis rubrapilaris, polymorphic light eruption, psoriasis, rhinophyma, rosacea,sclerosis, spider naevi, T-cell disorders, telangiectasia, urticaria andother vascular reactions.

(C) Musculoskeletal System.

The conditions or abnormalities of musculoskeletal system include thefollowing conditions or disorders, which may present as indicated, orotherwise: (1) osteoporosis: reduction of calcium in bone leading tothin bone and bone susceptible to fracture; (2) osteoarthritis:inflammation of joint cartilage provoking swelling and pain; (3)rheumatoid arthritis: inflammation of synovium and destruction ofcartilage, damage to heart, lungs, nerves and eyes; (4) ankylosingspondylitis: arthritis affecting sacroiliac joints and spine withinflammation and immovability; (5) bursitis: inflammation of bursa; (6)tendinitis: inflammation of tendon; (7) gout: recurrent acute arthritisfrom uric acid deposit; and (8) others, such as backache, bunion andhernia.

(D) Cutaneous System, and Others.

The cosmetic, dermatological or other conditions and disorders ofcutaneous system that my be treated with a composition of the presentinvention include deranged or disordered cutaneous or mucocutaneoustissue relevant to skin, nail and hair; oral, vaginal and anal mucosa;disturbed keratinization; inflammation; changes associated withintrinsic and extrinsic aging, and others which may or may not berelated to cutaneous system. The manifestations include acne; rosacea;age spots; blemished skin; blotches; cellulite; dermatoses; dermatitis;skin, nail and hair infections; dandruff; dryness or looseness of skin,nail and hair; xerosis; eczema; elastosis; herpes; hyperkeratosis;hyperpigmented skin; ichthyosis; keratoses; lentigines; melasmas;mottled skin; pseudofolliculitis barbae; photoaging and photodamage;pruritus; psoriasis; skin lines; stretch marks; thinning of skin, nailplate and hair; warts; wrinkles; oral or gum disease; irritated,inflamed, red, unhealthy, damaged or abnormal mucosa, skin, hair, nail,nostril, ear canal, anal or vaginal conditions; breakdown, defectivesynthesis or repair of dermal components; abnormal or diminishedsynthesis of collagen, glycosaminoglycans, proteoglycans and elastin, aswell as diminished levels of such components in the dermis; uneven skintone; uneven and rough surface of skin, nail and hair; loss or reductionof skin, nail and hair resiliency, elasticity and recoilability; laxity;lack of skin, nail and hair lubricants and luster; fragility andsplitting of nail and hair; yellowing skin; reactive, irritating ortelangiectatic skin; and dull and older-looking skin, nail and hair. Inaddition, N-(phosphonoalkyl)-amino acids can be used for general care ofskin, nail and hair; to improve skin texture and pores, flakiness andredness; to make skin soft, smooth, fresh, balanced, visibly clear,even-toned and brighter; to increase skin fullness and plumpness; andfor skin bleach and lightening and wound healing.

Skin, nail and hair infections can be caused by microorganisms whichinclude bacteria, fungi, yeasts, molds, parasites and viruses. Morespecifically, the bacterial infections can cause trichomycosisaxillaris, pitted keratolysis, erythrasma, impetigo, eethyma,furunculosis (boils), carbuncle, scalded skin syndrome, toxic shocksyndrome, erysipelas, cellulitis, necrotizing fasciitis, erysipeloid,cat-scratch disease (Rochalimaea henselae), syphilis, lyme disease(Borrelia burgdorferi), cutaneous anthrax (Bacillus anthracis),gonococcal septicaemia, inoculation tuberculosis, scrofuloderma,tuberculides, erythema induratum, leprosy (Mycobacterium leprae),mycobacterium ulcerans, leishmaniasis and acute paronychia. The viralinfections can cause viral warts (human papilloma virus), varicella(chickenpox), herpes zoster (varicella-zoster), herpes simplex(herpesvirus hominis), molluscum contagiosum, orf, AIDS (acquiredimmunodeficiency syndrome, human immunodeficiency virus, HIV),herpangina, mucocutaneous lymph node syndrome (Kawasaki's disease),Gianotti-Crosti syndrome (hepatitis B virus), measles, rubella anderythema infectiosum. The fungal infections can cause ringworm, tineapedis (athlete's foot), tinea nails, tinea hands, tinea groin, tineatrunk and limbs, tinea capitis (scalp), oral candidiasis, candidaintertrigo, genital candidiasis, chronic paronychia, chronicmucocutaneous candidiasis, pityriasis versicolor, histoplasmosis,coccidioidomycosis, blastomycosis, sporotrichosis, actinomycosis andmycetoma (madura foot).

The systemic administration includes parenteral injection, such asintravenous or intraarterial injection or infusion, subcutaneous,intramuscular or other injection, as well as oral, transdermal and otherroutes. The preferred systemic administration is oral administration.

Certain N-(phosphonoalkyl)-amino acids, related compounds andderivatives thereof can be represented by the following generic formula:

R₁CH(NR₂R₃)(CH₂)_(m)COR₄

wherein R₁ is H, an alkyl group having 1 to 19 carbon atoms, an arylgroup having 6 to 19 carbon atoms or an aralkyl group having 7 to 19carbon atoms; and R₁ can also carry —OH, —SH, —SCH₃, —NH₂, —NR₂R₃,—COR₄, —NHCONH₂, —NHC(═NR₂)NH₂, imidazole, pyrrolidine or otherheterocyclic group; m is an integer from 0 to 5; R₂ is a phosphonoalkylgroup having a formula (HO)₂PO(CH₂)_(n)—; R₃ is H or a phosphonoalkylgroup having a formula (HO)₂PO(CH₂)_(n)—; n is an integer from 1 to 9;R₄ is —NH₂ or —OR₅, R₅ is H, an alkyl group having 1 to 19 carbon atoms,an aryl group having 6 to 19 carbon atoms or an aralkyl group having 7to 19 carbon atoms; and the H attached to any carbon atom can besubstituted by I, F, Cl, Br, OH or an alkoxy group having 1 to 9 carbonatoms. Typical, but non-limiting phosphonoalkyl groups includephosphonomethyl, phosphonoethyl, phosphonopropyl, phosphonoisopropyl,phosphonobutyl, phosphonoisobutyl, phosphonopentyl, phosphonoisopentyl,phosphonooctyl and phosphonoisooctyl groups. The most preferred one isphosphonomethyl group. The N-(phosphonoalkyl)-amino acid, relatedcompound or derivative thereof can be present in a form as free acid,salt or partial salt with organic or inorganic alkali, amide, ester orlactone, as a stereoisomer such as in D, L, or DL form, or as anon-stereoisomer such as N-(phosphonoalkyl)-β-alanine. AmongN-(phosphonoalkyl)-amino acids, N-(phosphonoalkyl)-proline cannot berepresented by the above generic structure because the α-amino group ispart of the heterocyclic pyrrolidine ring. Therefore, N-(phosphonoalkyl)derivatives of proline such as N-(phosphonoalkyl)-proline,N-(phosphonoalkyl)-prolinamide and N-(phosphonoalkyl)-proline esterswill be represented by their chemical names. In the same manner,chemical names will be used if other compounds of the present inventioncannot be covered by the above generic structure.

Each of the amino groups of an amino acid excluding proline has twohydrogen atoms attached to the nitrogen atom, and can form a bis ordi(phosphonoalkyl)-amino acid such as N,N-bis(phosphonoalkyl)-alanineand N,N-bis(phosphonoalkyl)-tyrosine.

Most amino acids and related amino acids have only one amino groupattached to the alpha or other position of the carbon atom, and can haveonly one or two (phosphonoalkyl) groups attached to the amino group suchas N-(phosphonoalkyl)-serine and N,N-bis(phosphonoalkyl)-serine. Someamino acids and related amino acids, such as lysine, ornithine,arginine, histidine and tryptophan have additional amino, imino orguanidino groups in addition to the alpha amino group, and can form oneto four (phosphonoalkyl) groups, for example: N-(phosphonoalkyl)-aminoacids; N′-(phosphonoalkyl)-amino acids; N,N-bis(phosphonoalkyl)-aminoacids; N,N′-bis(phosphonoalkyl)-amino acids;N′,N′-bis(phosphonoalkyl)-amino acids; N,N,N′-tris(phosphonoalkyl)-aminoacids; N,N′,N′-tris(phosphonoalkyl)-amino acids andN,N,N′,N′-tetra(phosphonoalkyl)-amino acids. Non-limiting examples areN-(phosphonoalkyl)-lysine; N′-(phosphonoalkyl)-lysine;N,N-bis(phosphonoalkyl)-lysine; N,N′-bis(phosphonoalkyl)-lysine;N′,N′-bis(phosphonoalkyl)-lysine; N,N,N′-tris(phosphonoalkyl)-lysine;N,N′,N′-tris(phosphonoalkyl)-lysine andN,N,N′,N′-tetra(phosphonoalkyl)-lysine. All of the foregoing are to beincluded as “related compounds” or “derivatives.”

A more preferred N-(phosphonoalkyl) compound has a single phosphonoalkylradical attached to an amino group of an amino acid or related aminoacid, such as alpha N-(phosphonoalkyl)-lysine andN-(phosphonoalkyl)-γ-aminobutanoic acid.

Representative non-limiting mono-substituted common amino acids include:

N-(phosphonoalkyl)-alanine, N-(phosphonoalkyl)-arginine,N-(phosphonoalkyl)-asparagine, N-(phosphonoalkyl)-aspartic acid,N-(phosphonoalkyl)-cysteine, N-(phosphonoalkyl)-glycine,N-(phosphonoalkyl)-glutamic acid, N-(phosphonoalkyl)-glutamine,N-(phosphonoalkyl)-histidine, N-(phosphonoalkyl)-isoleucine,N-(phosphonoalkyl)-leucine, N-(phosphonoalkyl)-lysine,N-(phosphonoalkyl)-methionine, N-(phosphonoalkyl)-phenylalanine,N-(phosphonoalkyl)-proline, N-(phosphonoalkyl)-serine,N-(phosphonoalkyl)-threonine, N-(phosphonoalkyl)-tryptophan,N-(phosphonoalkyl)-tyrosine and N-(phosphonoalkyl)-valine.

Representative, non-limiting mono-substituted related amino acidsinclude:

N-(phosphonoalkyl)-β-alanine, N-(phosphonoalkyl)-γ-aminobutanoic acid,N-(phosphonoalkyl)-β-aminoisobutanoic acid, N-(phosphonoalkyl)-anserine,N-(phosphonoalkyl)-aminolevulinic acid, N-(phosphonoalkyl)-carnosine,N-(phosphonoalkyl)-canaline, N-(phosphonoalkyl)-canavanine,N-(phosphonoalkyl)-citrulline, N-(phosphonoalkyl)-creatine,N-(phosphonoalkyl)-creatinine, N-(phosphonoalkyl)-cysteine sulfinicacid, N-(phosphonoalkyl)-cystine, N-(phosphonoalkyl)-cycloserine,N-(phosphonoalkyl)-dopa[N-(phosphonoalkyl)-3,4-dihydroxyphenylalanine],N-(phosphonoalkyl)-dopamine(hydroxytyramine),N-(phosphonoalkyl)-ethionine, N-(phosphonoalkyl)-glutathione,N-(phosphonoalkyl)-guanidinoacetic acid,N-(phosphonoalkyl)-3-guanidinopropanoic acid,N-(phosphonoalkyl)-4-guanidinobutanoic acid,N-(phosphonoalkyl)-homocamosine, N-(phosphonoalkyl)-homocysteine,N-(phosphonoalkyl)-homoserine,N-(phosphonoalkyl)-4-hydroxyphenylglycine,N-(phosphonoalkyl)-hydroxyglutamic acid,N-(phosphonoalkyl)-hydroxylysine, N-(phosphonoalkyl)-hydroxyproline,N-(phosphonoalkyl)-hypusine, N-(phosphonoalkyl)-homoarginine,N-(phosphonoalkyl)-homocitrulline, N-(phosphonoalkyl)-homocystine,N-(phosphonoalkyl)-homophenylalanine, N-(phosphonoalkyl)-homotryptophan,N-(phosphonoalkyl)-hydroxylysine, N-(phosphonoalkyl)-hydroxyarginine,N-(phosphonoalkyl)-hydroxyhomoarginine,N-(phosphonoalkyl)-hydroxycitrulline,N-(phosphonoalkyl)-hydroxyomithine, N-(phosphonoalkyl)-hydroxyvaline,(phosphonoalkyl)-iminodiacetic acid, N-(phosphonoalkyl)-indospicine,N-(phosphonoalkyl)-methoxinine, N-(phosphonoalkyl)-methylarginine,N-(phosphonoalkyl)-methylhistidine, N-(phosphonoalkyl)-methyllysine,N-(phosphonoalkyl)-methylomithine, N-(phosphonoalkyl)-methylserine,N-(phosphonoalkyl)-norvaline, N-(phosphonoalkyl)-ornithine,N-(phosphonoalkyl)-oxalysine,N-(phosphonoalkyl)-penicillamine(N-phosphonoalkyl-dimethylcysteine),N-(phosphonoalkyl)-phenylglycine, N-(phosphonoalkyl)-3-phenylserine,N-(phosphonoalkyl)-sarcosine (N-phosphonoalkyl-N-methyl-glycine),N-(phosphonoalkyl)-serotonin (N-phosphonoalkyl-hydroxytryptamine),N-(phosphonoalkyl)-taurine, N-(phosphonoalkyl)-tryptamine andN-(phosphonoalkyl)-tyramine.

Representative, non-limiting di- or bis-substituted amino acids include:

N,N-bis(phosphonoalkyl)-alanine; N,N-bis(phosphonoalkyl)-arginine;N,N-bis(phosphonoalkyl)-asparagine; N,N-bis(phosphonoalkyl)-asparticacid; N,N-bis(phosphonoalkyl)-cysteine; N,N-bis(phosphonoalkyl)-glycine;N,N-bis(phosphonoalkyl)-glutamic acid;N,N-bis(phosphonoalkyl)-glutamine; N,N-bis(phosphonoalkyl)-histidine;N,N-bis(phosphonoalkyl)-isoleucine; N,N-bis(phosphonoalkyl)-leucine;N,N-bis(phosphonoalkyl)-lysine; N,N-bis(phosphonoalkyl)-methionine;N,N-bis(phosphonoalkyl)-phenylalanine; N,N-bis(phosphonoalkyl)-serine;N,N-bis(phosphonoalkyl)-threonine; N,N-bis(phosphonoalkyl)-tryptophan;N,N-bis(phosphonoalkyl)-tyrosine; N,N-bis(phosphonoalkyl)-valine;N,N′-bis(phosphonoalkyl)-arginine; N,N′-bis(phosphonoalkyl)-histidine;N,N′-bis(phosphonoalkyl)-lysine; N,N′-bis(phosphonoalkyl)-tryptophan.These di- or bis-substituted amino acids are within the category ofderivatives of amino acids.

Representative non-limiting di- or bis-substituted related amino acidsand derivatives include:

N,N-bis(phosphonoalkyl)-β-alanine;N,N-bis(phosphonoalkyl)-γ-aminobutanoic acid;N,N-bis(phosphonoalkyl)-α-aminoisobutanoic acid;N,N-bis(phosphonoalkyl)-anserine; N,N-bis(phosphonoalkyl)-aminolevulinicacid; N,N-bis(phosphonoalkyl)-carnosine;N,N-bis(phosphonoalkyl)-canaline; N,N-bis(phosphonoalkyl)-canavanine;N,N-bis(phosphonoalkyl)-citrulline; N,N-bis(phosphonoalkyl)-creatine;N,N-bis(phosphonoalkyl)-creatinine; N,N-bis(phosphonoalkyl)-cysteinesulfinic acid; N,N-bis(phosphonoalkyl)-cystine;N,N-bis(phosphonoalkyl)-cycloserine;N,N-bis(phosphonoalkyl)-dopa[N,N-bis(phosphonoalkyl)-3,4-dihydroxyphenylalanine];N,N-bis(phosphonoalkyl)-dopamine(hydroxytyramine);N,N-bis(phosphonoalkyl)-ethionine; N,N-bis(phosphonoalkyl)-glutathione;N,N-bis(phosphonoalkyl)-guanidinoacetic acid;N,N-bis(phosphonoalkyl)-3-guanidinopropanoic acid;N,N-bis(phosphonoalkyl)-4-guanidinobutanoic acid;N,N-bis(phosphonoalkyl)-homocamosine;N,N-bis(phosphonoalkyl)-homocysteine;N,N-bis(phosphonoalkyl)-homoserine;N,N-bis(phosphonoalkyl)-4-hydroxyphenylglycine;N,N-bis(phosphonoalkyl)-hydroxyglutamic acid;N,N-bis(phosphonoalkyl)-hydroxylysine;N,N-bis(phosphonoalkyl)-hydroxyproline;N,N-bis(phosphonoalkyl)-hypusine; N,N-bis(phosphonoalkyl)-homoarginine;N,N-bis(phosphonoalkyl)-homocitrulline;N,N-bis(phosphonoalkyl)-homocystine;N,N-bis(phosphonoalkyl)-homophenylalanine;N,N-bis(phosphonoalkyl)-homotryptophan;N,N-bis(phosphonoalkyl)-hydroxylysine;N,N-bis(phosphonoalkyl)-hydroxyarginine;N,N-bis(phosphonoalkyl)-hydroxyhomoarginine;N,N-bis(phosphonoalkyl)-hydroxycitrulline;N,N-bis(phosphonoalkyl)-hydroxyomithine;N,N-bis(phosphonoalkyl)-hydroxyvaline;N,N-bis(phosphonoalkyl)-indospicine;N,N-bis(phosphonoalkyl)-methoxinine;N,N-bis(phosphonoalkyl)-methylarginine;N,N-bis(phosphonoalkyl)-methylhistidine;N,N-bis(phosphonoalkyl)-methyllysine;N,N-bis(phosphonoalkyl)-methylomithine;N,N-bis(phosphonoalkyl)-methylserine; N,N-bis(phosphonoalkyl)-norvaline;N,N-bis(phosphonoalkyl)-ornithine; N,N-bis(phosphonoalkyl)-oxalysine;N,N-bis(phosphonoalkyl)-penicillamine(N-phosphonoalkyl-dimethylcysteine);N,N-bis(phosphonoalkyl)-phenylglycine;N,N-bis(phosphonoalkyl)-3-phenylserine;N,N-bis(phosphonoalkyl)-serotonin (N-phosphonoalkyl-hydroxytryptamine);N,N-bis(phosphonoalkyl)-taurine; N,N-bis(phosphonoalkyl)-tryptamine andN,N-bis(phosphonoalkyl)-tyramine. These di- or bis-substituted relatedamino acids are included with the invention as derivatives of relatedamino acids.

Any of the above phosphonoalkyl-amino acids, related compounds andderivatives thereof can be present as a free acid, salt or partial saltwith organic or inorganic alkali, lactone, amide, ester or instereoisomeric or non-stereoisomeric form.

As an illustration, N-(phosphonoalkyl)-proline includes for example,N-(phosphonoalkyl)-L-proline; N-(phosphonoalkyl)-L-proline sodium salt;N-(phosphonoalkyl)-L-prolinamide, N-(phosphonoalkyl)-L-proline methylester, N-(phosphonoalkyl)-L-proline ethyl ester,N-(phosphonoalkyl)-L-proline propyl ester andN-(phosphonoalkyl)-L-proline isopropyl ester.

The preferred phosphonoalkyl groups are phosphonomethyl, phosphonoethyl,phosphonopropyl, phosphonoisopropyl, phosphonobutyl, phosphonoisobutyl,phosphonopentyl, phosphonoisopentyl, phosphonooctyl andphosphonoisooctyl groups. Therefore, the preferred compounds of thepresent invention are N-(phosphonomethyl)-amino acids,N-(phosphonoethyl)-amino acids, N-(phosphonopropyl)-amino acids,N-(phosphonoisopropyl)-amino acids, N-(phosphonobutyl)-amino acids,N-(phosphonoisobutyl)-amino acids, N-(phosphonopentyl)-amino acids,N-(phosphonoisopentyl)-amino acids, N-(phosphonooctyl)-amino acids,N-(phosphonoisooctyl)-amino acids, and the related amino acid compoundsand derivatives thereof. The most preferred compounds areN-(phosphonomethyl)-amino acids, related compounds and derivativesthereof, in which R₂ is a (phosphonomethyl) group having the formula(HO)₂PO(CH₂), and R₃ is H or a phosphonomethyl group having the formula(HO)₂PO(CH₂) in the above generic structure.

Among N-(phosphonomethyl)-amino acids, N-(phosphonomethyl)-prolinecannot be represented by the above generic structure because the alphaamino group is part of the heterocyclic pyrrolidine ring. Therefore,N-(phosphonomethyl) derivatives of proline such asN-(phosphonomethyl)-proline, N-(phosphonomethyl)-prolinamide andN-(phosphonomethyl)-proline esters will be represented by their chemicalnames. In the same manner, chemical names will be used if othercompounds of the present invention cannot be covered by the abovegeneric structure.

As aforementioned, each of any of the amino groups of an amino acidexcluding proline has two hydrogen atoms attached to the nitrogen atom,and can form bis- or di-(phosphonomethyl)-amino acid such asN,N-bis(phosphonomethyl)-cysteine and N,N-bis(phosphonomethyl)-leucine.Most amino acids and related amino acids have only one amino groupattached to the alpha or other position of the carbon atom, and can haveonly one or two (phosphonomethyl) groups attached to the amino groupsuch as N-(phosphonomethyl)-serine and N,N-bis(phosphonomethyl)-serine.Some amino acids and related amino acids, such as lysine, ornithine,arginine, histidine and tryptophan have additional amino, imino orguanidino group in addition to the alpha amino group, and can form oneto four (phosphonomethyl) groups, such as N-(phosphonomethyl)-aminoacids; N′-(phosphonomethyl)-amino acids; N,N-bis(phosphonomethyl)-aminoacids; N,N′-bis(phosphonomethyl)-amino acids;N′N′-bis(phosphonomethyl)-amino acids;N,N,N′-tris(phosphonomethyl)-amino acids;N,N′N′-tris(phosphonomethyl)-amino acids andN,N,N′N′-tetra(phosphonomethyl)-amino acids. Non-limiting examples areN-(phosphonomethyl)-lysine; N′-(phosphonomethyl)-lysine;N,N-bis(phosphonomethyl)-lysine; N,N′-bis(phosphonomethyl)-lysine;N′,N′-bis(phosphonomethyl)-lysine; N,N,N′-tris(phosphonomethyl)-lysine;N,N′N′-tris(phosphonomethyl)-lysine andN,N,N′N′-tetra(phosphonomethyl)-lysine. A presently more preferredN-(phosphonomethyl) derivative is a single phosphonomethyl radicalattached to an amino group of an amino acid or related amino acid, suchas alpha N-(phosphonomethyl)-lysine andN-(phosphonomethyl)-γ-aminobutanoic acid.

The preferred mono-substituted common amino acids include:

N-(phosphonomethyl)-alanine, N-(phosphonomethyl)-arginine,N-(phosphonomethyl)-asparagine, N-(phosphonomethyl)-aspartic acid,N-(phosphonomethyl)-cysteine, N-(phosphonomethyl)-glycine,N-(phosphonomethyl)-glutamic acid, N-(phosphonomethyl)-glutamine,N-(phosphonomethyl)-histidine, N-(phosphonomethyl)-isoleucine,N-(phosphonomethyl)-leucine, N-(phosphonomethyl)-lysine,N-(phosphonomethyl)-methionine, N-(phosphonomethyl)-phenylalanine,N-(phosphonomethyl)-proline, N-(phosphonomethyl)-serine,N-(phosphonomethyl)-threonine, N-(phosphonomethyl)-tryptophan,N-(phosphonomethyl)-tyrosine and N-(phosphonomethyl)-valine. These arewithin the category of N-(phosphonomethyl)-amino acids.

The preferred mono-substituted related amino acids include:

N-(phosphonomethyl)-β-alanine, N-(phosphonomethyl)-γ-aminobutanoic acid,N-(phosphonomethyl)-β-aminoisobutanoic acid,N-(phosphonomethyl)-anserine, N-(phosphonomethyl)-aminolevulinic acid,N-(phosphonomethyl)-carnosine, N-(phosphonomethyl)-canaline,N-(phosphonomethyl)-canavanine, N-(phosphonomethyl)-citrulline,N-(phosphonomethyl)-creatine, N-(phosphonomethyl)-creatinine,N-(phosphonomethyl)-cysteine sulfinic acid, N-(phosphonomethyl)-cystine,N-(phosphonomethyl)-cycloserine, N-(phosphonomethyl)-dopa[N-(phosphonomethyl)-3,4-dihydroxyphenylalanine],N-(phosphonomethyl)-dopamine(hydroxytyramine),N-(phosphonomethyl)-ethionine, N-(phosphonomethyl)-glutathione,N-(phosphonomethyl)-guanidinoacetic acid,N-(phosphonomethyl)-3-guanidinopropanoic acid,N-(phosphonomethyl)-4-guanidinobutanoic acid,N-(phosphonomethyl)-homocamosine, N-(phosphonomethyl)-homocysteine,N-(phosphonomethyl)-homoserine,N-(phosphonomethyl)-4-hydroxyphenylglycine,N-(phosphonomethyl)-hydroxyglutamic acid,N-(phosphonomethyl)-hydroxylysine, N-(phosphonomethyl)-hydroxyproline,N-(phosphonomethyl)-hypusine, N-(phosphonomethyl)-homoarginine,N-(phosphonomethyl)-homocitrulline, N-(phosphonomethyl)-homocystine,N-(phosphonomethyl)-homophenylalanine,N-(phosphonomethyl)-homotryptophan, N-(phosphonomethyl)-hydroxylysine,N-(phosphonomethyl)-hydroxyarginine,N-(phosphonomethyl)-hydroxyhomoarginine,N-(phosphonomethyl)-hydroxycitrulline,N-(phosphonomethyl)-hydroxyornithine, N-(phosphonomethyl)-hydroxyvaline,N-(phosphonomethyl)iminodiacetic acid, N-(phosphonomethyl)-indospicine,N-(phosphonomethyl)-methoxinine, N-(phosphonomethyl)-methylarginine,N-(phosphonomethyl)-methylhistidine, N-(phosphonomethyl)-methyllysine,N-(phosphonomethyl)-methylomithine, N-(phosphonomethyl)-methylserine,N-(phosphonomethyl)-norvaline, N-(phosphonomethyl)-ornithine,N-(phosphonomethyl)-oxalysine,N-(phosphonomethyl)-penicillamine(N-phosphonomethyl-dimethylcysteine),N-(phosphonomethyl)-phenylglycine, N-(phosphonomethyl)-3-phenylserine,N-(phosphonomethyl)-sarcosine (N-phosphonomethyl-N-methyl-glycine),N-(phosphonomethyl)-serotonin (N-phosphonomethyl-hydroxytryptamine),N-(phosphonomethyl)-taurine, N-(phosphonomethyl)-tryptamine andN-(phosphonomethyl)-tyramine. These compounds are within the category ofN-(phosphonomethyl)-related amino acids, or simply, related compounds.

The preferred di- or bis-substituted common amino acids are:

N,N-bis(phosphonomethyl)-alanine; N,N-bis(phosphonomethyl)-arginine;N,N-bis(phosphonomethyl)-aspartic acid;N,N-bis(phosphonomethyl)-asparagines; N,N-bis(phosphonomethyl)-cysteine;N,N-bis(phosphonomethyl)-glycine; N,N-bis(phosphonomethyl)-glutamicacid; N,N-bis(phosphonomethyl)-glutamine;N,N-bis(phosphonomethyl)-histidine; N,N-bis(phosphonomethyl)-isoleucine;N,N-bis(phosphonomethyl)-leucine; N,N-bis(phosphonomethyl)-lysine;N,N-bis(phosphonomethyl)-methionine;N,N-bis(phosphonomethyl)-phenylalanine; N,N-bis(phosphonomethyl)-serine;N,N-bis(phosphonomethyl)-threonine; N,N-bis(phosphonomethyl)-tryptophan;N,N-bis(phosphonomethyl)-tyrosine; N,N-bis(phosphonomethyl)-valine;N,N′-bis(phosphonomethyl)-arginine; N,N′-bis(phosphonomethyl)-histidine;N,N′-bis(phosphonomethyl)-lysine andN,N′-bis(phosphonomethyl)-tryptophan. These compounds are within thecategory of derivatives.

The preferred di- or bis-substituted related amino acids and derivativesinclude:

N,N-bis(phosphonomethyl)-β-alanine;N,N-bis(phosphonomethyl)-γ-aminobutanoic acid;N,N-bis(phosphonomethyl)-β-aminoisobutanoic acid;N,N-bis(phosphonomethyl)-anserine;N,N-bis(phosphonomethyl)-aminolevulinic acid;N,N-bis(phosphonomethyl)-carnosine; N,N-bis(phosphonomethyl)-canaline;N,N-bis(phosphonomethyl)-canavanine;N,N-bis(phosphonomethyl)-citrulline; N,N-bis(phosphonomethyl)-creatine;N,N-bis(phosphonomethyl)-creatinine; N,N-bis(phosphonomethyl)-cysteinesulfinic acid; N,N-bis(phosphonomethyl)-cystine;N,N-bis(phosphonomethyl)-cycloserine; N,N-bis(phosphonomethyl)-dopa(3;N,N-bis(phosphonomethyl)-4-dihydroxyphenylalanine);N,N-bis(phosphonomethyl)-dopamine(hydroxytyramine);N,N-bis(phosphonomethyl)-ethionine;N,N-bis(phosphonomethyl)-glutathione;N,N-bis(phosphonomethyl)-guanidinoacetic acid;N,N-bis(phosphonomethyl)-3-guanidinopropanoic acid;N,N-bis(phosphonomethyl)-4-guanidinobutanoic acid;N,N-bis(phosphonomethyl)-homocarnosine;N,N-bis(phosphonomethyl)-homocysteine;N,N-bis(phosphonomethyl)-homoserine;N,N-bis(phosphonomethyl)-4-hydroxyphenylglycine;N,N-bis(phosphonomethyl)-hydroxyglutamic acid;N,N-bis(phosphonomethyl)-hydroxylysine;N,N-bis(phosphonomethyl)-hydroxyproline;N,N-bis(phosphonomethyl)-hypusine;N,N-bis(phosphonomethyl)-homoarginine;N,N-bis(phosphonomethyl)-homocitrulline;N,N-bis(phosphonomethyl)-homocystine;N,N-bis(phosphonomethyl)-homophenylalanine;N,N-bis(phosphonomethyl)-homotryptophan;N,N-bis(phosphonomethyl)-hydroxylysine;N,N-bis(phosphonomethyl)-hydroxyarginine;N,N-bis(phosphonomethyl)-hydroxyhomoarginine;N,N-bis(phosphonomethyl)-hydroxycitrulline;N,N-bis(phosphonomethyl)-hydroxyomithine;N,N-bis(phosphonomethyl)-hydroxyvaline;N,N-bis(phosphonomethyl)-indospicine;N,N-bis(phosphonomethyl)-methoxinine;N,N-bis(phosphonomethyl)-methylarginine;N,N-bis(phosphonomethyl)-methylhistidine;N,N-bis(phosphonomethyl)-methyllysine;N,N-bis(phosphonomethyl)-methylornithine;N,N-bis(phosphonomethyl)-methylserine;N,N-bis(phosphonomethyl)-norvaline; N,N-bis(phosphonomethyl)-ornithine;N,N-bis(phosphonomethyl)-oxalysine;N,N-bis(phosphonomethyl)-penicillamine(N-phosphonomethyl-dimethylcysteine);N,N-bis(phosphonomethyl)-phenylglycine;N,N-bis(phosphonomethyl)-3-phenylserine;N,N-bis(phosphonomethyl)-sarcosine (N-phosphonomethyl-N-methyl-glycine);N,N-bis(phosphonomethyl)-serotonin(N-phosphonomethyl-hydroxytryptamine); N,N-bis(phosphonomethyl)-taurine;N,N-bis(phosphonomethyl)-tryptamine; N,N-bis(phosphonomethyl)-tyramineand N,N′-bis(phosphonomethyl)-ornithine. These compounds are within thecategory of derivatives.

Any of the above phosphonomethyl-amino acids, related compounds andderivatives thereof can be present as a free acid, salt, or partial saltwith organic or inorganic alkali, lactone, amide, ester or instereoisomeric or non-stereoisomeric form.

As an illustration, N-(phosphonomethyl)-proline includes for example,N-(phosphonomethyl)-L-proline; N-(phosphonomethyl)-L-proline sodiumsalt; N-(phosphonomethyl)-L-prolinamide, N-(phosphonomethyl)-L-prolinemethyl ester, N-(phosphonomethyl)-L-proline ethyl ester,N-(phosphonomethyl)-L-proline propyl ester andN-(phosphonomethyl)-L-proline isopropyl ester.

Synthesis of N-(Phosphonomethyl)-Amino Acids and Related Compounds

Among different syntheses, the most convenient and simplest method isthe following process which is modified from the examples described inU.S. Pat. No. 3,799,758, the disclosure of which is hereby incorporatedby reference herein.

In general, most N-(phosphonomethyl)-amino acids and related compoundscan be synthesized by the following exemplary, non-limiting method.

An amino acid (1.1 mole) and chloromethyl phosphonic acid (1 mole) in300 ml of 8N NaOH were heated at 100° C. for 24 hours. After thereaction mixture was cooled to room temperature, 250 ml of 12N HCl wasslowly added with stirring while the container was cooled externallywith a cold-water bath. The mixture was filtered, and the filtrate wascooled with an ice-water bath. From the filtrate,N-(phosphonomethyl)-amino acid was obtained as a precipitate which waswashed with cold dilute HCl and cold water. The product thus obtainedwas identified by routine chemical methods.

The ester form of an N-(phosphonomethyl)-amino acid was synthesized by aconventional process which included heating theN-(phosphonomethyl)-amino acid in anhydrous alcohol containing HCl gas.Methyl, ethyl, propyl and isopropyl esters of anN-(phosphonomethyl)-amino acid were readily synthesized by the abovesimple process. For example, N-(phosphonomethyl)-L-proline ethyl ester,N-(phosphonomethyl)-L-tyrosine ethyl ester,N-(phosphonomethyl)-D-4-hydroxyphenylglycine ethyl ester,N-(phosphonomethyl)-glycine propyl ester and N-(phosphonomethyl)-glycineisopropyl ester were synthesized from their correspondentN-(phosphonomethyl)-amino acids by the above process.

The amide form of an N-(phosphonomethyl)-amino acid was also synthesizedby a conventional process which included reaction of anN-(phosphonomethyl)-amino acid methyl ester with ammonia gas inanhydrous methanol. For example, N-(phosphonomethyl)-glycinamide wassynthesized from N-(phosphonomethyl)-glycine methyl ester by the aboveprocess.

The N-(phosphonoalkyl)-amino acids and related compounds can besynthesized by the same procedure except that chloromethyl phosphonicacid is replaced by chloroalkyl phosphonic acid.

By using the above process the following specificN-(phosphonomethyl)-amino acids and related compounds have beensynthesized:

N-(phosphonomethyl)-asparagine, N-(phosphonomethyl)-cysteine,N-(phosphonomethyl)-glycine, N-(phosphonomethyl)-glutamic acid,N-(phosphonomethyl)-glutamine, N-(phosphonomethyl)-proline,N-(phosphonomethyl)-serine, N-(phosphonomethyl)-tyrosine,N-(phosphonomethyl)-γ-aminobutanoic acid, N-(phosphonomethyl)-creatine,N-(phosphonomethyl)-creatinine, N-(phosphonomethyl)-glutathione,N-(phosphonomethyl)-4-hydroxyphenylglycine,N-(phosphonomethyl)-ornithine, and N-(phosphonomethyl)-tyramine.

A composition comprising an N-(phosphonoalkyl)-amino acid, a relatedcompound or derivative of the present invention, preferably anN-(phosphonomethyl)-amino acid, a related compound or derivative thereofis believed to be cosmetically or therapeutically beneficial oreffective and can be administered topically or systemically to a mammal,including a human, subject in need of prevention or treatment ofcosmetic conditions, dermatological disorders, or diseases associatedwith the nervous, vascular, musculoskeletal or cutaneous system, orothers.

For topical administration, a composition comprising anN-(phosphonoalkyl)-amino acid, a related compound or derivative of thepresent invention, preferably an N-(phosphonomethyl)-amino acid arelated compound or derivative of the present invention, can betopically applied one to three times, and preferably twice, daily to thelesions or the cutaneous sites associated with cosmetic conditions ormedical disorders or diseases. The topical application can continueuntil the symptom, cosmetic condition, medical disorder or disease hasbeen eradicated or substantially improved. The treatment period dependson the condition or severity of the disorder or disease, and alsodepends on the individual subject. Examples of conditions, disorders anddiseases associated with nervous, vascular, musculoskeletal or cutaneoussystem, or others include, without limitation pains, pruritus,inflammation, erythema, dermatitis, acne, rosacea, eczema, severe dryskin, ichthyosis, age spots, psoriasis, wrinkles, photoaging skin,pigmented skin, and dark skin to be lightened.

As used herein, “percent” or “%” concerning an amount of an ingredientor component means weight percent of the ingredient or component withrespect to the overall composition, unless otherwise indicated.

For example, human subjects having severe dry skin or ichthyosis,topically applied 1%-5% N-(phosphonomethyl)-glycine creams to lesionsfor 2 to 3 weeks. After 2 to 3 weeks of topical application, the thickand scaly skin disappeared and the skin became smooth and normal inappearance. Clinical evaluation was judged to be 90% to 100% improvementcompared to the untreated condition or when using a vehicle control.

For systemic administration, a composition comprising anN-(phosphonoalkyl)-amino acid, a related compound or derivative of thepresent invention, preferably an N-(phosphonomethyl)-amino acid of thepresent invention, can be administered by injection, infusion or oralintake, or otherwise, with the preferred route being oraladministration. A composition comprising an N-(phosphonoalkyl)-aminoacid, a related compound or derivative of the present invention,preferably an N-(phosphonomethyl)-amino acid, a related compound orderivative can be taken orally one to three times, and preferably twice,daily for prevention or treatment of disorders and diseases associatedwith nervous, vascular, musculoskeletal or cutaneous system, or others.The oral administration can continue until the symptom, cosmeticcondition, medical disorder or disease has been eradicated orsubstantially improved. The symptoms or disorders include, withoutlimitation, pains, pruritus, inflammation, erythema, dermatitis, acne,eczema, dementia, Alzheimer's disease, joint pain or swelling, andarthritis. Oral dosages can be about 50 mg to about 500 mg daily,preferably divided into equal dosages of about 25 mg to about 250 mgtaken twice daily.

The particularly preferred N-(phosphonomethyl)-amino acids useful in theembodiments described herein, and that can be administered topically orsystemically include N-(phosphonomethyl)-asparagine,N-(phosphonomethyl)-asparaginamide, N-(phosphonomethyl)-glycine,N-(phosphonomethyl)-glycinamide, N-(phosphonomethyl)-glycine ethylester, N-(phosphonomethyl)-glycine propyl ester,N-(phosphonomethyl)-glycine isopropyl ester,N-(phosphonomethyl)-proline, N-(phosphonomethyl)-prolinamide,N-(phosphonomethyl)-proline ethyl ester, N-(phosphonomethyl)-prolinepropyl ester, N-(phosphonomethyl)-proline isopropyl ester,N-(phosphonomethyl)-glutamic acid, N-(phosphonomethyl)-glutamic aciddiethyl ester, N-(phosphonomethyl)-glutamine,N-(phosphonomethyl)-glutaminamide, N-(phosphonomethyl)-glutamine ethylester, N-(phosphonomethyl)-arginine, N-(phosphonomethyl)-argininamide,N-(phosphonomethyl)-arginine ethyl ester, N-(phosphonomethyl)-lysine,N-(phosphonomethyl)-lysinamide, N-(phosphonomethyl)-lysine ethyl ester,N-(phosphonomethyl)-creatine and N-(phosphonomethyl)-creatinine.

In accordance with preferred embodiments of the invention, a compositionis provided comprising at least one compound selected from the groupconsisting of an N-(phosphonoalkyl)-amino acid, a related compound orderivative of the present invention, preferably anN-(phosphonomethyl)-amino acid or derivative thereof, as free acid,ester, amide, lactone or salt form (which includes partial salts)present in a therapeutically or cosmetically effective amount and in apharmaceutically or cosmetically acceptable vehicle for topical orsystemic treatment of disorders associated with nervous, vascular,musculoskeletal or cutaneous system. In one embodiment of the invention,the composition further comprises a cosmetic, pharmaceutical or othertopically active agent for synergetic or synergistic effects.

These cosmetic, pharmaceutical or other topically active agent includesany one or more of an agent selected from hydroxyacids, ketoacids andrelated compounds; phenyl alpha acyloxyalkanoic acids and derivatives;N-acyl-aldosamines, N-acylamino acids and related N-acyl compounds;local analgesics and anesthetics; anti-acne agents; anti-bacterialagents; anti-yeast agents; anti-fungal agents; anti-viral agents;anti-infective agents; anti-dandruff agents; anti-dermatitis agents;anti-eczema agents; anti-histamine agents; anti-pruritic agents;anti-emetics; anti-motion sickness agents; anti-inflammatory agents;anti-hyperkeratotic agents; antiperspirants; anti-psoriatic agents;anti-rosacea agents; anti-seborrheic agents; hair conditioners and hairtreatment agents; anti-aging and anti-wrinkle agents; anti-anxietyagents; anti-convulsant agents; anti-depressant agents; sunblock andsunscreen agents; skin lightening agents; depigmenting agents;astringents; cleansing agents; corn, callus or wart removing agents;skin plumping agents; skin volumizing agents; skin firming agents;matrix metalloproteinase (MMP) inhibitors; topical cardiovascularagents; wound-healing agents; gum disease or oral care agents; aminoacids; peptides; dipeptides; tripeptides; glutathione and itsderivatives; oligopeptides; polypeptides; carbohydrates;aminocarbohydrates; vitamins; corticosteroids; tanning agents; hormonesand retinoids.

Non-limiting specific examples of particular cosmetic, pharmaceutical orother topically active agents, as stated or as free base, free acid,ester, amide, lactone or salt form, include for synergetic orsynergistic effects: abacavir, abciximab, acamprosate, acarbose,acebutolol, acetaminophen, acetaminosalol, acetazolamide, acetic acid,acetohydroxamic acid, N-acetylcysteine and its esters,N-acetylglutathione and its esters, acitretin, aclometasonedipropionate, acrivastine, acthrel, actidose, actigall, acyclovir,adalimumab, adapalene, adefovir dipivoxil, adenosine, agalsidase,albendazole, albumin, albuterol, aldesleukin, alefacept, alemtuzumab,alendronate, alfuzosin, alitretinoin, allantoin, allium, allopurinol,alloxanthine, almotriptan, alosetron, alpha tocopheral,alpha,-proteinase, alprazolam, alprenolol, alprostadil, alteplase,altretamine, aluminum acetate, aluminum chloride, aluminumchlorohydroxide, aluminum hydroxide, amantadine, amifostine, amiloride,aminacrine, amino acid, aminobenzoate, p-aminobenzoic acid, aminocaproicacid, aminohippurate, aminolevulinic acid, aminosalicylic acid,amiodarone, amitriptyline, amlodipine, amocarzine, amodiaquin,amorolfine, amoxapine, amoxicillin, amphetamine, amphotericin,ampicillin, amprenavir, anagrelide, anakinra, anastrozole, anisindione,anthralin, antihemophilic, antithrombin, anti-thymocyte, antivenin,apomorphine, aprepitant, aprotinin, arbutin, argatroban, aripiprazole,arnica, ascorbic acid and its esters, ascorbyl palmitate, aspirin,atazanavir, atenolol, atomoxetine, atorvastatin, atovaquone, atropine,azathioprine, azelaic acid, azelastine, azithromycin, baclofen,bacitracin, balsalazide, balsam, basiliximab, beclomethasonedipropionate, bemegride, benazepril, bendroflumethiazide, benzocaine,benzonatate, benzophenone, benzoyl peroxide, benztropine, bepridil, betacarotene, betamethasone dipropionate, betamethasone valerate, betaxolol,bethanechol, bevacizumab, bexarotene, bicalutamide, bimatoprost,bioflavonoids, biotin, biperiden, bisacodyl, bisoprolol, bivalirudin,bortezomib, bosentan, botulinum, brimonidine, brinzolamide,bromocriptine, brompheniramine, budesonide, bumetanide, bupivacaine,buprenorphine, bupropion, burimamide, buspirone, busulfan, butabarbital,butalbital, butenafine, butoconazole, butorphanol, butyl aminobenzoate,cabergoline, caffeic acid, caffeine, calcipotriene, calcitonin-salmon,calcitriol, calfactant, camellia sinensis, camphor, candesartancilexetil, capecitabine, capreomycin, capsaicin, captopril,carbamazepine, carbamide peroxide, carbidopa, carbinoxamine, cefditorenpivoxil, cefepime, cefpodoxime proxetil, celecoxib, cetirizine,cevimeline, chitosan, chlordiazepoxide, chlorhexidine, chloroquine,chlorothiazide, chloroxylenol, chlorpheniramine, chlorpromazine,chlorpropamide, ciclopirox, cilostazol, cimetidine, cinacalcet,ciprofloxacin, citalopram, citric acid, cladribine, clarithromycin,clemastine, clindamycin, clioquinol, clobetasol propionate, clocortolonepivalate, clomiphene, clonidine, clopidogrel, clotrimazole, clozapine,coal tar, coal tar extracts (LCD), codeine, cromolyn, crotamiton,cyclizine, cyclobenzaprine, cycloserine, cytarabine, dacarbazine,dalfopristin, dapsone, daptomycin, daunorubicin, deferoxamine,dehydroepiandrosterone, delavirdine, desipramine, desloratadine,desmopressin, desoximetasone, dexamethasone, dexmedetomidine,dexmethylphenidate, dexrazoxane, dextroamphetamine, diazepam,diclofenac, dicyclomine, didanosine, dihydrocodeine, dihydromorphine,diltiazem, 6,8-dimercaptooctanoic acid (dihydrolipoic acid),diphenhydramine, diphenoxylate, dipyridamole, disopyramide, dobutamine,dofetilide, dolasetron, donepezil, dopa esters, dopamide, dopamine,dorzolamide, doxepin, doxorubicin, doxycycline, doxylamine, doxepin,duloxetine, dyclonine, econazole, efalizumab, eflomithine, eletriptan,emtricitabine, enalapril, ephedrine, epinephrine, epinine, epirubicin,eptifibatide, ergotamine, erythromycin, escitalopram, esmolol,esomeprazole, estazolam, estradiol, etanercept, ethacrynic acid, ethinylestradiol, etidocaine, etomidate, famciclovir, famotidine, felodipine,fentanyl, ferulic acid, fexofenadine, flecamide, fluconazole,flucytosine, fluocinolone acetonide, fluocinonide, 5-fluorouracil,fluoxetine, fluphenazine, flurazepam, fluticasone propionate,fluvoxamine, formoterol, furosemide, galactarolactone, galactonic acid,galactonolactone, galantamine, gatifloxacin, gefitinib, gemcitabine,gemifloxacin, glucarolactone, gluconic acid, gluconolactone, glucuronicacid, glucuronolactone, glycolic acid, griseofulvin, guaifenesin,guanethidine, N-guanylhistamine, haloperidol, haloprogin,hexylresorcinol, homatropine, homosalate, hydralazine,hydrochlorothiazide, hydrocortisone, hydrocortisone 21-acetate,hydrocortisone 17-butyrate, hydrocortisone 17-valerate, hydrogenperoxide, hydromorphone, hydroquinone, hydroquinone monoether,hydroxyzine, hyoscyamine, hypoxanthine, ibuprofen, ichthammol,idarubicin, imatinib, imipramine, imiquimod, indinavir, indomethacin,infliximab, irbesartan, irinotecan, isoetharine, isoproterenol,itraconazole, kanamycin, ketamine, ketanserin, ketoconazole, ketoprofen,ketotifen, kojic acid, labetalol, lactic acid, lactobionic acid,lamivudine, lamotrigine, lansoprazole, letrozole, leuprolide,levalbuterol, levofloxacin, lidocaine, linezolid, lobeline, loratadine,loperamide, losartan, loxapine, lysergic diethylamide, mafenide, malicacid, maltobionic acid, mandelic acid, maprotiline, mebendazole,mecamylamine, meclizine, meclocycline, memantine, menthol, meperidine,mepivacaine, mequinol, mercaptopurine, mescaline, metanephrine,metaproterenol, metaraminol, metformin, methadone, methamphetamine,methotrexate, methoxamine, methyldopa esters, methyldopamide,

3,4-methylenedioxymethamphetamine, methyllactic acid, methyl nicotinate,methylphenidate, methyl salicylate, metiamide, metolazone, metoprolol,metronidazole, mexiletine, miconazole, midazolam, midodrine, miglustat,minocycline, minoxidil, mirtazapine, mitoxantrone, moexiprilat,molindone, monobenzone, morphine, moxifloxacin, moxonidine, mupirocin,nadolol, naftifine, nalbuphine, nalmefene, naloxone, naproxen,nefazodone, nelfinavir, neomycin, nevirapine, nicardipine, nicotine,nifedipine, nimodipine, nisoldipine, nitrofurantoin, nizatidine,norepinephrine, nystatin, octopamine, octreotide, octylmethoxycinnamate, octyl salicylate, ofloxacin, olanzapine, olmesartanmedoxomil, olopatadine, omeprazole, ondansetron, oxiconazole,oxotremorine, oxybenzone, oxybutynin, oxycodone, oxymetazoline, padimateO, palonosetron, pantothenic acid, pantoyl lactone, paroxetine,pemoline, penciclovir, penicillamine, penicillins, pentazocine,pentobarbital, pentostatin, pentoxifylline, pergolide, perindopril,permethrin, phencyclidine, phenelzine, pheniramine, phenmetrazine,phenobarbital, phenol, phenoxybenzamine, phentolamine, phenylephrine,phenylpropanolamine, phenyloin, physostigmine, pilocarpine,pimecrolimus, pimozide, pindolol, pioglitazone, pipamazine, piperonylbutoxide, pirenzepine, podofilox, povidone iodine, pramipexole,pramoxine, prazosin, prednisone, prenalterol, prilocalne, procainamide,procaine, procarbazine, promazine, promethazine, promethazinepropionate, propafenone, propoxyphene, propranolol, propylthiouracil,protriptyline, pseudoephedrine, pyrethrin, pyrilamine, pyrimethamine,quetiapine, quinapril, quinethazone, quinidine, quinupristin,rabeprazole, reserpine, resorcinol, retinal, 13-cis retinoic acid,retinoic acid, retinol, retinyl acetate, retinyl palmitate, ribavirin,ribonic acid, ribonolactone, rifampin, rifapentine, rifaximin, riluzole,rimantadine, risedronic acid, risperidone, ritodrine, rivastigmine,rizatriptan, ropinirole, ropivacaine, salicylamide, salicylic acid,salmeterol, scopolamine, selegiline, selenium sulfide, serotonin,sertaconazole, sertindole, sertraline, shale tar, sibutramine,sildenafil, sotalol, streptomycin, strychnine, sulconazole,sulfacetamide, sulfabenz, sulfabenzamide, sulfabromomethazine,sulfacetamide(sodium sulfacetamide), sulfachlorpyridazine, sulfacytine,sulfadiazine, sulfadimethoxine, sulfadoxine, sulfaguanole, sulfalene,sulfamethizole, sulfamethoxazole, sulfanilamide, sulfapyrazine,sulfapyridine, sulfasalazine, sulfasomizole, sulfathiazole,sulfisoxazole, sulfur, tacrolimus, tadalafil, tamsulosin, tartaric acid,tazarotene, tegaserod, telithromycin, telmisartan, temozolomide,tenofovir disoproxil, terazosin, terbinafine, terbutaline, terconazole,terfenadine, tetracaine, tetracycline, tetrahydrozoline, thalidomide,theobromine, theophylline, thiabendazole, thioctic acid (lipoic acid),thioridazine, thiothixene, thymol, tiagabine, timolol, timidazole,tioconazole, tirofiban, tizanidine, tobramycin, tocamide, tolazoline,tolbutamide, tolnaftate, tolterodine, tramadol, tranylcypromine,trazodone, triamcinolone acetonide, triamcinolone diacetate,triamcinolone hexacetonide, triamterene, triazolam, triclosan,triflupromazine, trimethoprim, trimipramine, tripelennamine,triprolidine, tromethamine, tropic acid, tyramine, undecylenic acid,urea, urocanic acid, ursodiol, valacyclovir, vardenafil, venlafaxine,verapamil, vitamin E acetate, voriconazole, warfarin, wood tar,xanthine, zafirlukast, zaleplon, zinc pyrithione, ziprasidone,zolmitriptan and zolpidem.

General Preparations

Compositions of the present invention comprising anN-(phosphonoalkyl)-amino acid, preferably an N-(phosphonomethyl)-aminoacid, a related compound or derivative of the present invention can beformulated as an injectable or infusible solution or other formulationor as a topical solution, gel, lotion, cream, ointment, shampoo, spray,stick, pad, powder, masque, mouth rinse or wash, vaginal gel orpreparation, or other form acceptable for use on skin, nail, hair, oralmucosa, vaginal or anal mucosa, mouth or gums.

To prepare a solution composition of the present invention, at least oneN-(phosphonoalkyl)-amino acid, preferably an N-(phosphonomethyl)-aminoacid, a related compound or derivative is dissolved in a solutionprepared from water, ethanol, propylene glycol, butylene glycol, and/orother pharmaceutically or cosmetically acceptable vehicle. Theconcentration of a single N-(phosphonoalkyl)-amino acid, preferably anN-(phosphonomethyl)-amino acid, a related compound or derivative, or thetotal concentration of all N-(phosphonomethyl)-amino acids where thecomposition comprises more than one N-(phosphonomethyl)-amino acid, canbe about 0.01% to about 99.9%, with a preferred concentration of about0.1% to about 50%, and a more preferred concentration of about 0.5% toabout 10%.

To prepare a topical composition in lotion, cream or ointment form, theN-(phosphonoalkyl)-amino acid, a related compound or derivative of thepresent invention, preferably an N-(phosphonomethyl)-amino acid, isfirst dissolved in water, ethanol, propylene glycol, and/or othervehicle, and the solution thus obtained is mixed with a desired base orpharmaceutically or cosmetically acceptable vehicle to make a lotion,cream or ointment. Typical ointments can be made readily with anoil-in-water emulsion, such as hydrophilic ointment U.S.P., as is wellknown to those skilled in the art in view of the present disclosure.Concentrations of the N-(phosphonoalkyl)-amino acid are the same asdescribed above regarding solutions.

A topical composition of the instant invention can also be formulated ina gel or shampoo form. A typical gel composition is formulated by theaddition of a gelling agent such as chitosan, methyl cellulose, ethylcellulose, polyvinyl alcohol, polyquatemiums, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer orammoniated glycyrrhizinate to a solution comprising theN-(phosphonoalkyl)-amino acid. The preferred concentration of thegelling agent may be about 0.1% to about 4%. In the preparation ofshampoo, the N-(phosphonoalkyl)-amino acid, related compound orderivative thereof is first dissolved in water or propylene glycol, andthe solution thus obtained is mixed with a shampoo base. Concentrationsof the N-(phosphonoalkyl)-amino acid, related compound or derivativethereof used in gel or shampoo form are the same as described aboveregarding solutions.

To prepare a combination composition for synergetic or synergisticeffects, a cosmetic, pharmaceutical or other agent is incorporated intoany one of the above compositions by dissolving or mixing the agent intothe formulation. Other forms of compositions of the present inventionfor delivery of the N-(phosphonoalkyl)-amino acid, a related compound orderivative of the present invention, preferably anN-(phosphonomethyl)-amino acid, are readily blended, prepared orformulated by those skilled in the art in view of the presentdisclosure. For systemic administration the N-(phosphonoalkyl)-aminoacid, a related compound or derivative of the present invention,preferably an N-(phosphonomethyl)-amino acid, can be formulated for oraladministration or for parenteral injection or infusion. In oralpreparations, the N-(phosphonoalkyl)-amino acid can be formulated intablet form or in gelatin capsules with or without mixing with gelatinpowder. Each tablet or capsule can contain about 10 mg to about 300 mgof the N-(phosphonomethyl)-amino acid as free acid, salt, amide, esteror lactone form. For parenteral injection or infusion, theN-(phosphonomethyl)-amino acid is prepared under sterilized conditions,usually in a concentration of about 1% to about 10% in water, propyleneglycol and/or non-aqueous vehicle.

The present invention will now be described in more detail withreference to the following non-limiting examples. In the initial testsfor comparative studies, a control vehicle was always included. It wasdiscovered that all the vehicle controls gave the same results as thatof the untreated skin sites; no detectable effects of the controls havebeen found as judged by clinical evaluation.

For subjective disorders such as pain, itch or the like, the therapeuticeffects were evaluated or judged by the subjects or patients; forexample, if the pain or itch had disappeared within hours or days. Forother detectable symptoms or syndromes, the therapeutic effects orimprovements were evaluated or judged by medical professionals.

Example 1

In one of the studies related to skin changes associated with aging,skin thickness was measured by micrometer calipers as follows:

The skin was grasped with a 2×6 cm metal hinge, the internal faces ofwhich were coated with emery cloth to prevent slippage, and manuallysqueezed to threshold subject discomfort. Combined thickness of twowhole-skin layers including thickness of the two hinge leaves wasmeasured with micrometer calipers. Thickness of the two hinge leaves wassubtracted to determine the actual thickness of the two whole-skinlayers. Triplicate measurements on treated sites were done and anaverage number was used for calculation of the skin thickness.

Example 2

N-(phosphonomethyl)-glycine (5 g) was suspended in water (30 ml) andpropylene glycol (10 ml), and concentrated ammonium hydroxide (2 ml) wasadded with stirring. The suspension became a clear solution, and wasmixed with hydrophilic ointment (oil-in-water emulsion, 53 g). The whitecream thus formulated had pH 3.8 and contained 5%N-(phosphonomethyl)-glycine. A male subject, age 35, who had X-linkedichthyosis with severe dry skin, having thick and rough skin withadherent scales, topically applied the above 5%N-(phosphonomethyl)-glycine cream to an involved skin site twice dailyfor two weeks. After one week of topical application, the adherentscales disappeared, and the skin became smooth and had 50% improvementin contrast to the untreated or vehicle control as judged by clinicalevaluation. After two weeks of topical application, the treated skinbecame normal in appearance, and had 100% improvement in contrast to theuntreated or vehicle control as judged by clinical evaluation. The aboveresults show that a representative N-(phosphonomethyl)-amino acid wouldbe therapeutically effective for topical treatment of disturbedkeratinization and hyperkeratotic conditions including dry skin, severedry skin, ichthyosis, calluses, keratoses, acne, rosacea, blemishedskin, psoriasis and age spots.

Example 3

N-(phosphonomethyl)imino-diacetic acid (5 g) was suspended in water (15ml) and propylene glycol (10 ml), and concentrated ammonium hydroxide (3ml) was added with stirring. The suspension became a clear solution, andwas mixed with hydrophilic ointment (oil-in-water emulsion 67 g). Thewhite cream thus formulated had pH 3.5 and contained 5%N-(phosphonomethyl)imino-diacetic acid.

A male subject, age 35, who had X-linked ichthyosis with severe dryskin, having thick and rough skin with adherent scales, topicallyapplied the above 5% N-(phosphonomethyl)imino-diacetic acid cream to aninvolved skin site twice daily for two weeks. After one week of topicalapplication, most adherent scales disappeared and the skin had 50%improvement in contrast to the untreated or vehicle control as judged byclinical evaluation. After two weeks of topical application, the scalesdisappeared completely and the treated skin became smooth, and had 90%improvement in contrast to the untreated or vehicle control as judged byclinical evaluation.

The above results show that another representativeN-(phosphonomethyl)-amino acid would be therapeutically effective fortopical treatment of disturbed keratinization and hyperkeratoticconditions including dry skin, severe dry skin, ichthyosis, calluses,keratoses, acne, rosacea, blemished skin, psoriasis and age spots.

Example 4

N-(phosphonomethyl)-glycine ethyl ester (5 g) was dissolved in warmwater (20 ml) and propylene glycol (20 ml), and the solution thusobtained was mixed with hydrophilic ointment (oil-in-water emulsion, 55g). The white cream thus formulated had pH 1.2 and contained 5%N-(phosphonomethyl)-glycine ethyl ester.

A male subject, age 86, had chronic plaque psoriasis with erythema,moderately thick and silvery scales. The subject topically applied twicedaily the above white cream containing 5% N-(phosphonomethyl)-glycineethyl ester to one psoriatic lesion for two weeks. At the end of twoweeks, the erythema and silvery scales improved substantially, and thetreated skin had 50% improvement in contrast to the untreated or vehiclecontrol as judged by clinical evaluation.

Example 5

N-(phosphonomethyl)-L-tyrosine (5 g) was dissolved in warm propyleneglycol (40 ml), and the solution thus obtained was mixed withhydrophilic ointment (oil-in-water emulsion, 55 g). The white cream thusformulated had pH 2.3 and contained 5% N-(phosphonomethyl)-L-tyrosine.

A male subject, age 35, who had X-linked ichthyosis with severe dryskin, having thick and rough skin with adherent scales, topicallyapplied the above 5% N-(phosphonomethyl)-L-tyrosine cream to an involvedskin site twice daily for 12 days. After 12 days of topical application,most adherent scales disappeared and the skin became smooth, and had 75%improvement in contrast to the untreated or vehicle control as judged byclinical evaluation.

The above results show that another representativeN-(phosphonomethyl)-amino acid would be therapeutically effective fortopical treatment of disturbed keratinization and hyperkeratoticconditions including dry skin, severe dry skin, ichthyosis, calluses,keratoses, acne, rosacea, blemished skin, psoriasis and age spots.

Example 6

N-(phosphonomethyl)-L-proline (5 g) was suspended in water (20 ml), andconcentrated ammonium hydroxide (0.8 ml) was added. The solution thusobtained was mixed with hydrophilic ointment (oil-in-water emulsion,74.2 g). The white cream thus formulated had pH 3.2 and contained 5%N-(phosphonomethyl)-L-proline. Under the same procedure, a white creamcontaining 10% N-(phosphonomethyl)-L-proline was formulated fromN-(phosphonomethyl)-L-proline (10 g), water (20 ml), concentratedammonium hydroxide (1 ml), and hydrophilic ointment (oil-in-wateremulsion, 69 g).

A male subject, age 86, had chronic plaque psoriasis with erythema,moderately thick and silvery scales. The subject topically applied twicedaily the above white cream containing 10% N-(phosphonomethyl)-L-prolineto one psoriatic lesion for two weeks. At the end of two weeks, theerythema and silvery scales improved very substantially, and the treatedskin had 75% improvement in contrast to the untreated or vehicle controlas judged by clinical evaluation.

The above results show that yet another representativeN-(phosphonomethyl)-amino acid would be therapeutically effective fortopical treatment of disturbed keratinization and inflammatoryconditions including erythema, eczema, dermatitis, dermatoses, itch,psoriasis, acne and rosacea.

Example 7

N-(phosphonomethyl)-DL-asparagine (6 g) was dissolved in warm water (30ml) and propylene glycol (10 ml), and the solution thus obtained wasmixed with hydrophilic ointment (oil-in-water emulsion, 54 g). The whitecream thus formulated had pH 2.2 and contained 6%N-(phosphonomethyl)-DL-asparagine.

N-(phosphonomethyl)-DL-asparagine (5 g) was dissolved in warm water (30ml) and propylene glycol (10 ml), and the solution thus obtained wasmixed with hydrophilic ointment (oil-in-water emulsion, 55 g). The whitecream thus formulated had pH 2.2 and contained 5%N-(phosphonomethyl)-DL-asparagine.

A male subject, age 36, who had X-linked ichthyosis having thick andrough skin with adherent scales, topically applied the 5%N-(phosphonomethyl)-DL-asparagine cream to an involved skin site twicedaily for three weeks. After one week of topical application, mostadherent scales disappeared and the treated site appeared smooth. Theskin had 75% improvement in contrast to the untreated or vehicle controlas judged by clinical evaluation. After three weeks of topicalapplication, the scales disappeared completely and the treated site feltsmooth and normal in appearance. The skin had 100% improvement incontrast to the untreated or vehicle control as judged by clinicalevaluation.

The above results show that another N-(phosphonomethyl)-amino acid wouldbe therapeutically effective for topical treatment of disturbedkeratinization and hyperkeratotic conditions including dry skin, severedry skin, ichthyosis, calluses, keratoses, acne, rosacea, blemishedskin, psoriasis and age spots.

Example 8

A male subject, age 36, who had hyperpigmented dark skin, topicallyapplied 5% N-(phosphonomethyl)-DL-asparagine cream prepared according toExample 7 to an involved skin site twice daily for four weeks. After twoweeks of topical application, the treated site had mild depigmentationand showed lighter skin color as compared to untreated skin site. Thetreated site was 25% lighter in skin color in contrast to the untreatedor vehicle control as judged by clinical evaluation. After four weeks oftopical application, the treated site had substantial reduction in skinpigmentation. The treated site was 50% lighter in contrast to theuntreated or vehicle control in skin color as judged by clinicalevaluation.

The above results show that a representative N-(phosphonomethyl)-aminoacid would be effective for topical treatment of hyperpigmented skin,age spots, melasma, lentigines, mottled skin, aging related skinchanges, and would be topically effective for skin lightening.

Example 9

N-(phosphonomethyl)-glycine propyl ester (10 g) was dissolved in warmwater (20 ml), propylene glycol (10 ml) and 2-amino-2-methyl-1-propanol(5 ml). The clear solution thus obtained was mixed with hydrophilicointment (oil-in-water emulsion, 55 g). The white cream thus formulatedhad pH 5.1, and contained 10% N-(phosphonomethyl)-glycine propyl ester.Under the same procedure, a white cream containing 5%N-(phosphonomethyl)-glycine propyl ester was formulated fromN-(phosphonomethyl)-glycine propyl ester (5 g), warm water (20 ml),propylene glycol (10 ml), 2-amino-2-methyl-1-propanol (2.5 ml) andhydrophilic ointment (oil-in-water emulsion, 62.5 g).

A male subject, age 86, had chronic plaque psoriasis with erythema,moderately thick and silvery scales. The subject topically applied twicedaily the above white cream containing 5% N-(phosphonomethyl)-glycinepropyl ester to one psoriatic lesion for two weeks. At the end of twoweeks, the erythema and silvery scales improved very substantially, andthe treated skin had 75% improvement in contrast to the untreated orvehicle control as judged by clinical evaluation.

The above results show that still another representativeN-(phosphonomethyl)-amino acid derivative would be therapeuticallyeffective for topical treatment of disturbed keratinization andinflammatory conditions including erythema, eczema, dermatitis,dermatoses, itch, psoriasis, acne and rosacea.

Example 10

N-(phosphonomethyl)-glycine isopropyl ester (10 g) was dissolved inwater (10 ml), propylene glycol (20 ml) and meglumine(N-methyl-D-glucamine, 4 g). The solution thus obtained was mixed withhydrophilic ointment (oil-in-water emulsion, 56 g). The white cream thusformulated had pH 1.1, and contained 10% N-(phosphonomethyl)-glycineisopropyl ester. Under the same procedure, a white cream containing 5%N-(phosphonomethyl)-glycine isopropyl ester was formulated fromN-(phosphonomethyl)-glycine isopropyl ester (5 g), water (10 ml),propylene glycol (20 ml), meglumine (2 g) and hydrophilic ointment (63g).

A male subject, age 86, had chronic plaque psoriasis with erythema,moderately thick and silvery scales. The subject topically applied twicedaily the above white cream containing 5% N-(phosphonomethyl)-glycineisopropyl ester to one psoriatic lesion for a week. At the end of oneweek, the erythema and silvery scales improved substantially, and thetreated skin had 50% improvement in contrast to the untreated or vehiclecontrol as judged by clinical evaluation.

Example 11

N-(phosphonomethyl)-glycinamide (5 g) was dissolved in water (10 ml) andpropylene glycol (30 ml), and the mixture thus obtained was mixed withhydrophilic ointment (oil-in-water emulsion, 55 g). The white cream thusformulated had pH 2.1 and contained 5% N-(phosphonomethyl)-glycinamide.Under the same procedure, a white cream containing 8%N-(phosphonomethyl)-glycinamide was formulated fromN-(phosphonomethyl)-glycinamide (8 g), water (10 ml), propylene glycol(30 ml) and hydrophilic ointment (52 g).

A male subject, age 86, had chronic plaque psoriasis with erythema,moderately thick and silvery scales. The subject topically applied twicedaily the above white cream containing 8%N-(phosphonomethyl)-glycinamide to one psoriatic lesion for three weeks.At the end of three weeks, the erythema and silvery scales disappearedalmost completely, and the treated skin had 90% improvement in contrastto the untreated or vehicle control as judged by clinical evaluation.

The above results show that another representativeN-(phosphonomethyl)-amino acid derivative would be therapeuticallyeffective for topical treatment of disturbed keratinization andinflammatory conditions including erythema, eczema, dermatitis,dermatoses, itch, psoriasis, acne and rosacea.

Example 12

N-(phosphonomethyl)-L-tyrosine ethyl ester (5 g) was dissolved in warmpropylene glycol (20 ml) and water (10 ml). The solution thus obtainedwas mixed with hydrophilic ointment (oil-in-water emulsion, 65 g). Thewhite cream thus formulated had pH 1.2 and contained 5%N-(phosphonomethyl)-L-tyrosine ethyl ester.

A male subject, age 36, who had X-linked ichthyosis having thick andrough skin with adherent scales, topically applied the above 5%N-(phosphonomethyl)-L-tyrosine ethyl ester cream to an involved skinsite twice daily for one week. After one week of topical application,most adherent scales disappeared and the treated skin had 25%improvement in contrast to the untreated or vehicle control as judged byclinical evaluation.

The above results show that another N-(phosphonomethyl)-amino acid wouldbe therapeutically effective for topical treatment of disturbedkeratinization and hyperkeratotic conditions including dry skin, severedry skin, ichthyosis, calluses, keratoses, acne, rosacea, blemishedskin, psoriasis and age spots.

A male subject, age 86, had chronic plaque psoriasis with erythema,moderately thick and silvery scales. The subject topically applied twicedaily the above white cream containing 5% N-(phosphonomethyl)-L-tyrosineethyl ester to one psoriatic lesion for two weeks. At the end of twoweeks, the erythema and silvery scales improved noticeably and thetreated skin had 25% improvement in contrast to the untreated or vehiclecontrol as judged by clinical evaluation.

The above results show that another representativeN-(phosphonomethyl)-amino acid derivative would be therapeuticallyeffective for topical treatment of disturbed keratinization andinflammatory conditions including erythema, eczema, dermatitis,dermatoses, itch, psoriasis, acne and rosacea.

Example 13

N-(phosphonomethyl)-D-4-hydroxyphenylglycine (5 g) was dissolved inwater (10 ml) and propylene glycol (20 ml), and the mixture thusobtained was mixed with hydrophilic ointment (oil-in-water emulsion, 65g). The white cream thus formulated had pH 2.4, and contained 5%N-(phosphonomethyl)-D-4-hydroxyphenylglycine. Under the same procedure,a white cream containing 10%N-(phosphonomethyl)-D-4-hydroxyphenylglycine was formulated fromN-(phosphonomethyl)-D-4-hydroxyphenylglycine (10 g), water (10 ml),propylene glycol (20 ml), and hydrophilic ointment (60 g).

A male subject, age 86, had chronic plaque psoriasis with erythema,moderately thick and silvery scales. The subject topically applied twicedaily the above white cream containing 10%N-(phosphonomethyl)-D-4-hydroxyphenylglycine to one psoriatic lesion fortwo weeks. At the end of two weeks, the erythema and silvery scalesimproved very substantially, and the treated skin had 70% improvement incontrast to the untreated or vehicle control as judged by clinicalevaluation.

Example 14

N-(phosphonomethyl)-L-serine (6 g) was dissolved in warm propyleneglycol (10 ml) and water (30 ml). The solution thus obtained was mixedwith hydrophilic ointment (oil-in-water emulsion, 54 g). The white creamthus formulated had pH 1.7 and contained 6%N-(phosphonomethyl)-L-serine.

Example 15

N-(phosphonomethyl)-L-proline ethyl ester (8 g) was dissolved in water(10 ml), propylene glycol (20 ml) and ethylenediamine (4 ml). Thesolution thus obtained was mixed with hydrophilic ointment (oil-in-wateremulsion, 58 g). The white cream thus formulated had pH 5.9, andcontained 8% N-(phosphonomethyl)-L-proline ethyl ester.

A male subject, age 74, having itchy eczema on his right thigh,topically applied the above 8% N-(phosphonomethyl)-L-proline ethyl estercream. The itch disappeared within a few minutes after the topicalapplication. The treated skin did not itch for the next 8 hours.Therapeutic evaluation was judged to be 100% effective in contrast tothe untreated or vehicle control for immediate relief of itch.

The above result shows that a representative N-(phosphonomethyl)-aminoacid derivative would be therapeutically effective for topical treatmentof disturbed keratinization and inflammatory conditions includingerythema, eczema, dermatitis, dermatoses, itch, psoriasis, acne androsacea.

Example 16

N-(phosphonomethyl)-L-serine ethyl ester (6 g) was dissolved in warmpropylene glycol (30 ml). The solution thus obtained was mixed withhydrophilic ointment (oil-in-water emulsion, 64 g). The white cream thusformulated had pH 1.3 and contained 6% N-(phosphonomethyl)-L-serineethyl ester.

Example 17

N-(phosphonomethyl)-creatine (7 g) was dissolved in water (30 ml) andpropylene glycol (10 ml), and the solution thus obtained was mixed withhydrophilic ointment (oil-in-water emulsion, 53 g). The white cream thusformulated had pH 1.8 and contained 7% N-(phosphonomethyl)-creatine.Under the same procedure, a white cream containing 5%N-(phosphonomethyl)-creatine was formulated fromN-(phosphonomethyl)-creatine (5 g), water (30 ml), propylene glycol (10ml), and hydrophilic ointment or oil-in-water emulsion (55 g). Under thesame procedure, a white cream containing 10%N-(phosphonomethyl)-creatine was formulated fromN-(phosphonomethyl)-creatine (10 g), water (30 ml), propylene glycol (10ml), and hydrophilic ointment (oil-in-water emulsion, 50 g).

A male subject, age 86, had chronic plaque psoriasis with erythema,moderately thick and silvery scales. The subject topically applied twicedaily the above white cream containing 5% N-(phosphonomethyl)-creatineto one psoriatic lesion for two weeks. At the end of two weeks, theerythema and silvery scales improved substantially, and the treated skinhad 50% improvement in contrast to the untreated or vehicle control asjudged by clinical evaluation.

Example 18

A male subject, age 74, having itchy eczema on his left leg, topicallyapplied 7% N-(phosphonomethyl)-creatine cream prepared according toExample 17. The itch disappeared within a few minutes after the topicalapplication. The treated skin did not itch for the next 8 hours.Therapeutic evaluation was judged to be 100% effective in contrast tothe untreated or vehicle control for immediate relief of itch.

The above results show that a representative N-(phosphonomethyl)-aminoacid would be therapeutically effective for topical treatment ofdisturbed keratinization and inflammatory conditions including erythema,eczema, dermatitis, dermatoses, itch, psoriasis, acne and rosacea.

Example 19

N-(phosphonomethyl)-creatine (2 g) was dissolved in (98 ml) of asolution prepared from water (40 parts by volume), ethanol (40 parts byvolume) and propylene glycol (20 parts by volume). The composition thusprepared had pH 2.5 and contained 2% N-(phosphonomethyl)-creatine insolution.

N-(phosphonomethyl)-creatine (5 g) was dissolved in (95 ml) solutionprepared from water (40 parts by volume), ethanol (40 parts by volume)and propylene glycol (20 parts by volume). The composition thus preparedcontained 5% N-(phosphonomethyl)-creatine in solution.

A male subject, age 35, who had X-linked ichthyosis having thick andrough skin with adherent scales, topically applied the above 5%N-(phosphonomethyl)-creatine solution to an involved skin site onceevery other with occlusion for two weeks. After 10 days of topicalapplication, most adherent scales disappeared and the skin had 50%improvement in contrast to the untreated or vehicle control as judged byclinical evaluation. After two weeks of topical application, the scalesdisappeared completely and the treated skin became normal in appearance,and had 100% improvement in contrast to the untreated or vehicle controlas judged by clinical evaluation.

The above results show that another representativeN-(phosphonomethyl)-amino acid would be therapeutically effective fortopical treatment of disturbed keratinization and hyperkeratoticconditions including dry skin, severe dry skin, ichthyosis, calluses,keratoses, acne, rosacea, blemished skin, psoriasis and age spots.

Example 20

N-(phosphonomethyl)-tyramine (5 g) was suspended in warm propyleneglycol (30 ml), and water (5 ml), and the mixture thus obtained wasmixed with hydrophilic ointment (oil-in-water emulsion, 60 g). The whitecream thus formulated had pH 2.1 and contained 5%N-(phosphonomethyl)-tyramine.

A male subject, age 86, had chronic plaque psoriasis with erythema,moderately thick and silvery scales. The subject topically applied twicedaily the above white cream containing 5% N-(phosphonomethyl)-tyramineto one psoriatic lesion for two weeks. At the end of two weeks, theerythema and silvery scales improved substantially, and the treated skinhad 50% improvement in contrast to the untreated or vehicle control asjudged by clinical evaluation.

Example 21

N-(phosphonomethyl)-DL-asparagine (5 g) was dissolved in (95 ml) of asolution prepared from water (40 parts by volume), ethanol (40 parts byvolume) and propylene glycol (20 parts by volume). The composition thusprepared had 2.7, and contained 5% N-(phosphonomethyl)-DL-asparagine insolution.

A male subject, age 36, who had hyperpigmented dark skin, topicallyapplied the above 5% N-(phosphonomethyl)-DL-asparagine solution to aninvolved skin site once every other day with occlusion for ten days.After seven days of topical application, the treated site had milddepigmentation and showed lighter skin color as compared to untreatedskin site. The treated site was 25% lighter in skin color as judged byclinical evaluation. After ten days of topical application, the treatedsite had substantial reduction in skin pigmentation. The treated sitewas 50% lighter in skin color in contrast to the untreated or vehiclecontrol as judged by clinical evaluation.

The above results show that a representative N-(phosphonomethyl)-aminoacid would be effective for topical treatment of hyperpigmented skin,age spots, melasma, lentigines, mottled skin, aging related skinchanges, and would be topically effective for skin lightening.

Example 22

A male subject, age 36, who had X-linked ichthyosis having thick andrough skin with adherent scales, topically applied the 5%N-(phosphonomethyl)-DL-asparagine solution prepared according to Example21 to an involved skin site once every other day under occlusion forthree weeks. After one week of topical application, most adherent scalesdisappeared and the treated site appeared smooth. The skin had 75%improvement in contrast to the untreated or vehicle control as judged byclinical evaluation. After three weeks of topical application, thetreated skin site appeared normal, and the skin had 100% improvement incontrast to the untreated or vehicle control as judged by clinicalevaluation.

The above results show that a representative N-(phosphonomethyl)-aminoacid would be therapeutically effective for topical treatment ofdisturbed keratinization and hyperkeratotic conditions including dryskin, severe dry skin, ichthyosis, calluses, keratoses, acne, rosacea,blemished skin, psoriasis and age spots.

Example 23

N-(phosphonomethyl)-creatine (5 g) was dissolved in (95 ml) solutionprepared from water (40 parts by volume), ethanol (40 parts by volume)and propylene glycol (20 parts by volume). The composition thus preparedhad pH 2.5, and contained 5% N-(phosphonomethyl)-creatine in solution.

A male subject, age 36, who had hyperpigmented dark skin, topicallyapplied the above 5% N-(phosphonomethyl)-creatine solution to aninvolved skin site once every other day with occlusion for two weeks.After seven days of topical application, the treated site had milddepigmentation and showed lighter skin color as compared to untreatedskin site. The treated site was 25% lighter in skin color in contrast tothe untreated or vehicle control as judged by clinical evaluation. Aftertwo weeks of topical application, the treated site had very substantialreduction in skin pigmentation. The treated site was 75% lighter in skincolor in contrast to the untreated or vehicle control as judged byclinical evaluation.

The above results show that a representative N-(phosphonomethyl)-aminoacid would be effective for topical treatment of hyperpigmented skin,age spots, melasma, lentigines, mottled skin, aging related skinchanges, and would be topically effective for skin lightening.

Example 24

N-(phosphonomethyl)-glycinamide (5 g) was dissolved in (95 ml) of asolution prepared from water (40 parts by volume), ethanol (40 parts byvolume) and propylene glycol (20 parts by volume). The composition thusprepared had pH 2.5, and contained 5% N-(phosphonomethyl)-glycinamide insolution.

A male subject, age 36, who had hyperpigmented dark skin, topicallyapplied the above 5% N-(phosphonomethyl)-glycinamide solution to aninvolved skin site once every other day with occlusion for two weeks.After seven days of topical application, the treated site had milddepigmentation and showed lighter skin color as compared to untreatedskin site. The treated site was 25% lighter in skin color in contrast tothe untreated or vehicle control as judged by clinical evaluation. Aftertwo weeks of topical application, the treated site had substantialreduction in skin pigmentation. The treated site was 50% lighter in skincolor in contrast to the untreated or vehicle control as judged byclinical evaluation.

The above results show that another representativeN-(phosphonomethyl)-amino acid derivative would be effective for topicaltreatment of hyperpigmented skin, age spots, melasma, lentigines,mottled skin, aging related skin changes, and would be topicallyeffective for skin lightening.

Example 25

A male subject, age 36, who had X-linked ichthyosis having thick andrough skin with adherent scales, topically applied 5%N-(phosphonomethyl)-glycinamide solution prepared according to Example24 to an involved skin site once every other day for three weeks. Afterone week of topical application, most adherent scales disappeared andthe treated site appeared smooth. The skin had 75% improvement incontrast to the untreated or vehicle control as judged by clinicalevaluation. After three weeks of topical application, the treated skinsite appeared normal, and the skin had 100% improvement in contrast tothe untreated or vehicle control as judged by clinical evaluation.

The above results show that another N-(phosphonomethyl)-amino acidderivative would be therapeutically effective for topical treatment ofdisturbed keratinization and hyperkeratotic conditions including dryskin, severe dry skin, ichthyosis, calluses, keratoses, acne, rosacea,blemished skin, psoriasis and age spots.

Example 26

N-(phosphonomethyl)-L-glutamine (5 g) was dissolved in (95 ml) of asolution prepared from water (40 parts by volume), ethanol (40 parts byvolume) and propylene glycol (20 parts by volume). The composition thusprepared had pH 2.0, and contained 5% N-(phosphonomethyl)-L-glutamine insolution.

A male subject, age 36, who had hyperpigmented dark skin, topicallyapplied the above 5% N-(phosphonomethyl)-L-glutamine solution to aninvolved skin site once every other day with occlusion for two weeks.After two weeks of topical application, the treated site had substantialreduction in skin pigmentation. The treated site had 50% lighter in skincolor in contrast to the untreated or vehicle control as judged byclinical evaluation.

The above result shows that another representativeN-(phosphonomethyl)-amino acid would be effective for topical treatmentof hyperpigmented skin, age spots, melasma, lentigines, mottled skin,aging related skin changes, and would be topically effective for skinlightening.

Example 27

A male subject, age 36, who had X-linked ichthyosis having thick andrough skin with adherent scales, topically applied 5%N-(phosphonomethyl)-L-glutamine solution prepared according to Example26 to an involved skin site once every other day for three weeks. Aftertwo weeks of topical application, most scales disappeared and thetreated site felt nearly smooth, and the skin had 75% improvement incontrast to the untreated or vehicle control as judged by clinicalevaluation. After three weeks of topical application, the treated siteappeared normal, and the skin had 100% improvement in contrast to theuntreated or vehicle control as judged by clinical evaluation.

The above results show that another representativeN-(phosphonomethyl)-amino acid would be therapeutically effective fortopical treatment of disturbed keratinization and hyperkeratoticconditions including dry skin, severe dry skin, ichthyosis, calluses,keratoses, acne, rosacea, blemished skin, psoriasis and age spots.

Example 28

N-(phosphonomethyl)-tyramine (5 g) and concentrated ammonium hydroxidesolution (1 ml) were dissolved in a solution (94 ml) prepared from water(40 parts by volume), ethanol (40 parts by volume) and propylene glycol(20 parts by volume). The composition thus prepared had pH 7.1 andcontained 5% N-(phosphonomethyl)-tyramine in solution.

A male subject, age 36, who had X-linked ichthyosis having thick andrough skin with adherent scales, topically applied the above 5%N-(phosphonomethyl)-tyramine solution to an involved skin site onceevery other day under occlusion for a week. After one week of topicalapplication, most adherent scales disappeared and the treated siteappeared smooth. The skin had 75% improvement in contrast to theuntreated or vehicle control as judged by clinical evaluation.

The above results show that another representativeN-(phosphonomethyl)-amino acid would be therapeutically effective fortopical treatment of disturbed keratinization and hyperkeratoticconditions including dry skin, severe dry skin, ichthyosis, calluses,keratoses, acne, rosacea, blemished skin, psoriasis and age spots.

Example 29

N-(phosphonomethyl)-glutamine (3 g) was dissolved in (97 ml) of asolution prepared from water (80 parts by volume) and propylene glycol(20 parts by volume). The composition thus prepared had pH 2.0 andcontained 3% N-(phosphonomethyl)-L-glutamine in solution.

N-(phosphonomethyl)-L-glutamine (10 g) was dissolved in warm water (20ml) and propylene glycol (10 ml), and the solution thus obtained wasmixed with hydrophilic ointment (oil-in-water emulsion, 60 g). The whitecream thus formulated had pH 1.3 and contained 10%N-(phosphonomethyl)-L-glutamine.

A male subject, age 74, having itchy eczema on his left thigh, topicallyapplied the above 10% N-(phosphonomethyl)-glutamine. The itchdisappeared within a few minutes after the topical application. Thetreated skin did not itch for the next 8 hours. Therapeutic evaluationwas judged to be 100% effective in contrast to the untreated or vehiclecontrol for immediate relief of itch.

The above results show that a representative N-(phosphonomethyl)-aminoacid would be therapeutically effective for topical treatment ofdisturbed keratinization and inflammatory conditions including erythema,eczema, dermatitis, dermatoses, itch, psoriasis, acne and rosacea.

Example 30

N-(phosphonomethyl)-L-glutamine (6 g) was dissolved in warm water (40ml), and the solution thus obtained was mixed with hydrophilic ointment(oil-in-water emulsion, 54 g). The white cream thus formulated had pH1.5 and contained 6% N-(phosphonomethyl)-L-glutamine.

Example 31

N-(phosphonomethyl)-L-glutamic acid (8 g) was dissolved in water (20 ml)and propylene glycol (10 ml), and the solution thus obtained was mixedwith hydrophilic ointment (oil-in-water emulsion, 62 g). The white creamthus formulated had pH 2.4 and contained 8%N-(phosphonomethyl)-L-glutamic acid.

A male subject, age 86, had chronic plaque psoriasis with erythema,moderately thick and silvery scales. The subject topically applied twicedaily the above white cream containing 8% N-(phosphonomethyl)-L-glutamicacid to one psoriatic lesion for two weeks. At the end of two weeks, theerythema and silvery scales improved substantially and the treated skinhad 50% improvement in contrast to the untreated or vehicle control asjudged by clinical evaluation.

The above results show that another representativeN-(phosphonomethyl)-amino acid derivative would be therapeuticallyeffective for topical treatment of disturbed keratinization andinflammatory conditions including erythema, eczema, dermatitis,dermatoses, itch, psoriasis, acne and rosacea.

Example 32

N-(phosphonomethyl)-γ-aminobutanoic acid (10 g) was dissolved in water(20 ml) and propylene glycol (10 ml), and the solution thus obtained wasmixed with hydrophilic ointment (oil-in-water emulsion, 60 g). The whitecream thus formulated had pH 1.9 and contained 10%N-(phosphonomethyl)-γ-aminobutanoic acid.

Example 33

N-(phosphonomethyl)-L-glutathione (5 g) was dissolved in (95 ml) of awarm solution prepared from water (40 parts by volume), ethanol (40parts by volume) and propylene glycol (20 parts by volume). Thecomposition thus prepared had pH 2.3 and contained 5%N-(phosphonomethyl)-L-glutathione in solution.

Example 34

N-(phosphonomethyl)-L-cysteine (5 g) was dissolved in (95 ml) of a warmsolution prepared from water (40 parts by volume), ethanol (40 parts byvolume) and propylene glycol (20 parts by volume). The composition thusprepared had pH 2.7 and contained 5% N-(phosphonomethyl)-L-cysteine insolution.

Example 35

N-(phosphonomethyl)-guanidinoacetic acid[N-(phosphonomethyl)-glycocyamine, 1 g] was dissolved in a solution (99ml) prepared from water (80 parts by volume) and propylene glycol (20parts by volume). The composition thus prepared had pH 2.1, andcontained 1% N-(phosphonomethyl)-guanidinoacetic acid in solution.

Example 36

The following is a typical process for preparing a compositioncomprising an N-(phosphonomethyl)-amino acid or derivative for oraladministration.

N-(Phosphonomethyl)-glycine crystals were converted to fine powder bygrinding with mortar and pestle. Lilly® gelatin capsules size No. 1,were filled to the top with N-(phosphonomethyl)-glycine powder withoutmixing with gelatin powder. Each capsule thus prepared contained 300 mgN-(phosphonomethyl)-glycine.

A subject can take orally one or two capsules per day for systemicadministration to alleviate or improve cosmetic conditions, or medicaldisorders, symptoms or syndromes associated with the nervous, vascular,musculoskeletal or cutaneous system, or others.

Example 37

N-(Phosphonomethyl)-L-tyrosine crystals were converted to fine powder bygrinding with mortar and pestle. Lilly® gelatin capsules size No. 1,were filled to the top with N-(phosphonomethyl)-L-tyrosine powderwithout mixing with gelatin powder. Each capsule thus prepared contained120 mg N-(phosphonomethyl)-L-tyrosine.

A subject can take orally one or two capsules per day for systemicadministration to alleviate or improve cosmetic conditions, or medicaldisorders, symptoms or syndromes associated with the nervous, vascular,musculoskeletal or cutaneous system, or others.

Example 38

N-(Phosphonomethyl)-L-serine crystals were converted to fine powder bygrinding with mortar and pestle. Lilly® gelatin capsules size No. 1,were filled to the top with N-(phosphonomethyl)-L-serine powder withoutmixing with gelatin powder. Each capsule thus prepared contained 130 mgN-(phosphonomethyl)-L-serine.

A subject can take orally one or two capsules per day for systemicadministration to alleviate or improve cosmetic conditions, or medicaldisorders, symptoms or syndromes associated with the nervous, vascular,musculoskeletal or cutaneous system, or others.

Example 39

N-(Phosphonomethyl)-L-proline crystals were converted to fine powder bygrinding with mortar and pestle. Lilly® gelatin capsules size No. 1,were filled to the top with N-(phosphonomethyl)-L-proline powder withoutmixing with gelatin powder. Each capsule thus prepared contained 150 mgN-(phosphonomethyl)-L-proline.

A subject can take orally one or two capsules per day for systemicadministration to alleviate or improve cosmetic conditions, or medicaldisorders, symptoms or syndromes associated with the nervous, vascular,musculoskeletal or cutaneous system, or others.

Example 40

N-(Phosphonomethyl)-creatinine (5 g) was dissolved in 95 ml of asolution prepared from water (80 parts by volume) and propylene glycol(20 parts by volume). The liquid composition thus prepared had pH 4.8and contained 5% N-(phosphonomethyl)-creatinine. This composition wouldbe topically effective for treatment or prevention of cosmeticconditions or medical disorders, symptoms or syndromes associated withnervous, vascular, musculoskeletal or cutaneous system, or others.

Example 41

N-(Phosphonomethyl)-L-ornithine (8 g) was dissolved in 92 ml of asolution prepared from water (80 parts by volume) and propylene glycol(20 parts by volume). The liquid composition thus prepared had pH 1.4and contained 8% N-(phosphonomethyl)-L-ornithine. This composition wouldbe topically effective for treatment or prevention of cosmeticconditions or medical disorders, symptoms or syndromes associated withnervous, vascular, musculoskeletal or cutaneous system, or others.

Example 42

N,N-Bis(phosphonomethyl)-glycine (2.5 g) was dissolved in water (10 ml),and the solution thus obtained was mixed with hydrophilic ointment(oil-in-water emulsion, 87.5 g). The white cream thus formulated had pH1.3 and contained 2.5% N,N-bis(phosphonomethyl)-glycine.

Example 43

N-(phosphonomethyl)-4-guanidinobutanoic acid (5 g) was dissolved inwater (20 ml), and the solution thus obtained was mixed with hydrophilicointment (oil-in-water emulsion, 75 g). The white cream thus formulatedhad pH 1.8 and contained 5% N-(phosphonomethyl)-4-guanidinobutanoicacid.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications within the spirit and scope of thepresent invention as defined by the appended claims.

1. An N-(phosphonoalkyl)-amino acid, a related compound or a derivativethereof, the N-(phosphonoalkyl)-amino acid, related compound orderivative thereof being in a form as a free acid, salt, partial salt,lactone, amide or ester, or in stereoisomeric or non-stereoisomericform, other than N-(phosphonomethyl)-glycine orN,N-bis(phosphonomethyl)-glycine.
 2. The compound of claim 1, selectedfrom the group consisting of N-(phosphonoalkyl)-proline and a compoundor derivative thereof having the following formula:R₁CH(NR₂R₃)(CH₂)_(m)COR₄ wherein R₁ is H, an alkyl group having 1 to 19carbon atoms, an aryl group having 6 to 19 carbon atoms or an aralkylgroup having 7 to 19 carbon atoms; and R₁ can also carry —OH, —SH,—SCH₃, —NH₂, —NR₂R₃, —COR₄, —NHCONH₂, —NHC(═NR₂)NH₂, imidazole,pyrrolidine or other heterocyclic group; m is an integer from 0 to 5; R₂is a phosphonoalkyl group having a formula (HO)₂PO(CH₂)_(n)—; R₃ is H ora phosphonoalkyl group having a formula (HO)₂PO(CH₂)_(n)—; n is aninteger from 1 to 9; R₄ is —NH₂ or —OR₅, R₅ is H, an alkyl group having1 to 19 carbon atoms, an aryl group having 6 to 19 carbon atoms or anaralkyl group having 7 to 19 carbon atoms; and the H attached to anycarbon atom can be substituted by I, F, Cl, Br, OH or an alkoxy grouphaving 1 to 9 carbon atoms; and wherein the N-(phosphonoalkyl)-aminoacid, related compound or derivative thereof is in a form as a freeacid, salt, partial salt, lactone, amide or ester, or in astereoisomeric or non-stereoisomeric form; provided that the compound isnot N-(phosphonomethyl)-glycine or N,N-bis(phosphonomethyl)-glycine. 3.The compound of claim 1, wherein the compound is anN-(phosphonoalkyl)-amino acid.
 4. The compound of claim 1, wherein thephosphonoalkyl of the N-(phosphonoalkyl)-amino acid compound, relatedcompound or compound derived therefrom is selected from the groupconsisting of phosphonomethyl, phosphonoethyl, phosphonopropyl,phosphonoisopropyl, phosphonobutyl, phosphonoisobutyl, phosphonopentyl,phosphonoisopentyl, phosphonooctyl and phosphonoisooctyl.
 5. Thecompound of claim 4, wherein the phosphonoalkyl of theN-(phosphonoalkyl)-amino acid compound, related compound or compoundderived therefrom is phosphonomethyl.
 6. The compound of claim 1,wherein the compound is an N-(phosphonomethyl)-amino acid.
 7. Thecompound of claim 5, wherein the N-(phosphonomethyl)-amino acid in aform as a free acid, salt, partial salt, lactone, amide or ester, or ina stereoisomeric or non-stereoisomeric form, is selected from the groupconsisting of N-(phosphonomethyl)-alanine, N-(phosphonomethyl)-arginine,N-(phosphonomethyl)-asparagine, N-(phosphonomethyl)-aspartic acid,N-(phosphonomethyl)-cysteine, N-(phosphonomethyl)-glutamic acid,N-(phosphonomethyl)-glutamine, N-(phosphonomethyl)-histidine,N-(phosphonomethyl)-isoleucine, N-(phosphonomethyl)-leucine,N-(phosphonomethyl)-lysine, N-(phosphonomethyl)-methionine,N-(phosphonomethyl)-phenylalanine, N-(phosphonomethyl)-proline,N-(phosphonomethyl)-serine, N-(phosphonomethyl)-threonine,N-(phosphonomethyl)-tryptophan, N-(phosphonomethyl)-tyrosine andN-(phosphonomethyl)-valine.
 8. The compound of claim 1, wherein theN-(phosphonoalkyl)-amino acid compound, related compound or compoundderived therefrom in a form as a free acid, salt, partial salt, lactone,amide or ester, or in stereoisomeric or non-stereoisomeric form, isselected from the group consisting of N-(pphosphonomethl)-β-alanine,N-(phosphonomethyl)-γ-aminobutanoic acid,N-(phosphonomethyl)-β-aminoisobutanoic acid,N-(phosphonomethyl)-anserine, N-(phosphonomethyl)-aminolevulinic acid,N-(phosphonomethyl)-carnosine, N-(phosphonomethyl)-canaline,N-(phosphonomethyl)-canavanine, N-(phosphonomethyl)-citrulline,N-(phosphonomethyl)-creatine, N-(phosphonomethyl)-creatinine,N-(phosphonomethyl)-cysteine sulfinic acid, N-(phosphonomethyl)-cystine,N-(phosphonomethyl)-cycloserine,N-(phosphonomethyl)-dopa[N-(phosphonomethyl)-3,4-dihydroxyphenylalanine],N-(phosphonomethyl)-dopamine(hydroxytyramine),N-(phosphonomethyl)-ethionine, N-(phosphonomethyl)-glutathione,N-(phosphonomethyl)-guanidinoacetic acid,N-(phosphonomethyl)-3-guanidinopropanoic acid,N-(phosphonomethyl)-4-guanidinobutanoic acid,N-(phosphonomethyl)-homocarnosine, N-(phosphonomethyl)-homocysteine,N-(phosphonomethyl)-homoserine,N-(phosphonomethyl)-4-hydroxyphenylglycine,N-(phosphonomethyl)-hydroxyglutamic acid,N-(phosphonomethyl)-hydroxylysine, N-(phosphonomethyl)-hydroxyproline,N-(phosphonomethyl)-hypusine, N-(phosphonomethyl)-homoarginine,N-(phosphonomethyl)-homocitrulline, N-(phosphonomethyl)-homocystine,N-(phosphonomethyl)-homophenylalanine,N-(phosphonomethyl)-homotryptophan, N-(phosphonomethyl)-hydroxylysine,N-(phosphonomethyl)-hydroxyarginine,N-(phosphonomethyl)-hydroxyhomoarginine,N-(phosphonomethyl)-hydroxycitrulline,N-(phosphonomethyl)-hydroxyomithine, N-(phosphonomethyl)-hydroxyvaline,N-(phosphonomethyl)-indospicine, N-(phosphonomethyl)-methoxinine,N-(phosphonomethyl)-methylarginine, N-(phosphonomethyl)-methylhistidine,N-(phosphonomethyl)-methyllysine, N-(phosphonomethyl)-methylomithine,N-(phosphonomethyl)-methylserine, N-(phosphonomethyl)-norvaline,N-(phosphonomethyl)-ornithine, N-(phosphonomethyl)-oxalysine,N-(phosphonomethyl)-penicillamine(N-phosphonomethyl-dimethylcysteine),N-(phosphonomethyl)-phenylglycine, N-(phosphonomethyl)-3-phenylserine,N-(phosphonomethyl)-sarcosine (N-phosphonomethyl-N-methyl-glycine),N-(phosphonomethyl)-serotonin (N-phosphonomethyl-hydroxytryptamine),N-(phosphonomethyl)-taurine, N-(phosphonomethyl)-tryptamine andN-(phosphonomethyl)-tyramine.
 9. The compound of claim 1, wherein thecompound is selected from the group consisting ofN-(phosphonomethyl)-asparagine, N-(phosphonomethyl)-asparaginamide,N-(phosphonomethyl)-γ-aminobutanoic acid, N-(phosphonomethyl)-arginine,N-(phosphonomethyl)-argininamide, N-(phosphonomethyl)-arginine ethylester, N-(phosphonomethyl)-creatine, N-(phosphonomethyl)-creatinine,N-(phosphonomethyl)-cysteine, N-(phosphonomethyl)-glutamic acid,N-(phosphonomethyl)-glutamic acid diethyl ester,N-(phosphonomethyl)-glutamine, N-(phosphonomethyl)-glutaminamide,N-(phosphonomethyl)-glutamine ethyl ester,N-(phosphonomethyl)-glutathione,N-(phosphonomethyl)-4-hydroxyphenylglycine, N-(phosphonomethyl)-lysine,N-(phosphonomethyl)-lysinamide, N-(phosphonomethyl)-lysine ethyl ester,N-(phosphonomethyl)-ornithine, N-(phosphonomethyl)-proline,N-(phosphonomethyl)-prolinamide, N-(phosphonomethyl)-proline ethylester, N-(phosphonomethyl)-proline propyl ester,N-(phosphonomethyl)-proline isopropyl ester, N-(phosphonomethyl)-serine,N-(phosphonomethyl)-tyrosine and N-(phosphonomethyl)-tyramine.
 10. Acomposition comprising an N-(phosphonoalkyl)-amino acid, a relatedcompound or a derivative thereof, the N-(phosphonoalkyl)-amino acid,related compound or derivative thereof being in a form as a free acid,salt, partial salt, lactone, amide or ester, or in stereoisomeric ornon-stereoisomeric form, and a cosmetically or pharmaceuticallyacceptable vehicle for topical or systemic administration to a mammaliansubject.
 11. The composition of claim 10, wherein the related compoundor derivative is an N,N-bis(phosphonoalkyl)-amino acid or anN,N′-bis(phosphonoalkyl)-amino acid.
 12. The composition of claim 11,wherein the related compound or derivative is anN,N-bis(phosphonomethyl)-amino acid or anN,N′-bis(phosphonomethyl)-amino acid.
 13. The composition of claim 12,wherein the N,N-bis(phosphonomethyl)-amino acid orN,N-bis(phosphonomethyl)-amino acid in a form as a free acid, salt,partial salt, lactone, amide or ester, or in stereoisomeric ornon-stereoisomeric form, is selected from the group consisting ofN,N-bis(phosphonomethyl)-alanine; N,N-bis(phosphonomethyl)-arginine;N,N-bis(phosphonomethyl)-aspartic acid;N,N-bis(phosphonomethyl)-asparagine; N,N-bis(phosphonomethyl)-cysteine;N,N-bis(phosphonomethyl)-glycine; N,N-bis(phosphonomethyl)-glutamicacid; N,N-bis(phosphonomethyl)-glutamine;N,N-bis(phosphonomethyl)-histidine; N,N-bis(phosphonomethyl)-isoleucine;N,N-bis(phosphonomethyl)-leucine; N,N-bis(phosphonomethyl)-lysine;N,N-bis(phosphonomethyl)-methionine;N,N-bis(phosphonomethyl)-phenylalanine; N,N-bis(phosphonomethyl)-serine;N,N-bis(phosphonomethyl)-threonine; N,N-bis(phosphonomethyl)-tryptophan;N,N-bis(phosphonomethyl)-tyrosine; N,N-bis(phosphonomethyl)-valine;N,N′-bis(phosphonomethyl)-arginine; N,N′-bis(phosphonomethyl)-histidine;N,N′-bis(phosphonomethyl)-lysine andN,N′-bis(phosphonomethyl)-tryptophan.
 14. The composition of claim 12,wherein the related compound or compound derived therefrom in a form asa free acid, salt, partial salt, lactone, amide or ester, or instereoisomeric or non-stereoisomeric form, is selected from the groupconsisting of N,N-bis(phosphonomethyl)-β-alanine;N,N-bis(phosphonomethyl)-γ-aminobutanoic acid;N,N-bis(phosphonomethyl)-β-aminoisobutanoic acid;N,N-bis(phosphonomethyl)-anserine;N,N-bis(phosphonomethyl)-aminolevulinic acid;N,N-bis(phosphonomethyl)-carnosine; N,N-bis(phosphonomethyl)-canaline;N,N-bis(phosphonomethyl)-canavanine;N,N-bis(phosphonomethyl)-citrulline; N,N-bis(phosphonomethyl)-creatine;N,N-bis(phosphonomethyl)-creatinine; N,N-bis(phosphonomethyl)-cysteinesulfinic acid; N,N-bis(phosphonomethyl)-cystine;N,N-bis(phosphonomethyl)-cycloserine; N,N-bis(phosphonomethyl)-dopa (3;N,N-bis(phosphonomethyl)-4-dihydroxyphenylalanine);N,N-bis(phosphonomethyl)-dopamine(hydroxytyramine);N,N-bis(phosphonomethyl)-ethionine;N,N-bis(phosphonomethyl)-glutathione;N,N-bis(phosphonomethyl)-guanidinoacetic acid;N,N-bis(phosphonomethyl)-3-guanidinopropanoic acid;N,N-bis(phosphonomethyl)-4-guanidinobutanoic acid;N,N-bis(phosphonomethyl)-homocamosine;N,N-bis(phosphonomethyl)-homocysteine;N,N-bis(phosphonomethyl)-homoserine;N,N-bis(phosphonomethyl)-4-hydroxyphenylglycine;N,N-bis(phosphonomethyl)-hydroxyglutamic acid;N,N-bis(phosphonomethyl)-hydroxylysine;N,N-bis(phosphonomethyl)-hydroxyproline;N,N-bis(phosphonomethyl)-hypusine;N,N-bis(phosphonomethyl)-homoarginine;N,N-bis(phosphonomethyl)-homocitrulline;N,N-bis(phosphonomethyl)-homocystine;N,N-bis(phosphonomethyl)-homophenylalanine;N,N-bis(phosphonomethyl)-homotryptophan;N,N-bis(phosphonomethyl)-hydroxylysine;N,N-bis(phosphonomethyl)-hydroxyarginine;N,N-bis(phosphonomethyl)-hydroxyhomoarginine;N,N-bis(phosphonomethyl)-hydroxycitrulline;N,N-bis(phosphonomethyl)-hydroxyomithine;N,N-bis(phosphonomethyl)-hydroxyvaline;N,N-bis(phosphonomethyl)-indospicine;N,N-bis(phosphonomethyl)-methoxinine;N,N-bis(phosphonomethyl)-methylarginine;N,N-bis(phosphonomethyl)-methylhistidine;N,N-bis(phosphonomethyl)-methyllysine;N,N-bis(phosphonomethyl)-methylornithine;N,N-bis(phosphonomethyl)-methylserine;N,N-bis(phosphonomethyl)-norvaline; N,N-bis(phosphonomethyl)-ornithine;N,N-bis(phosphonomethyl)-oxalysine;N,N-bis(phosphonomethyl)-penicillamine(N-phosphonomethyl-dimethylcysteine);N,N-bis(phosphonomethyl)-phenylglycine;N,N-bis(phosphonomethyl)-3-phenylserine;N,N-bis(phosphonomethyl)-sarcosine (N-phosphonomethyl-N-methyl-glycine);N,N-bis(phosphonomethyl)-serotonin(N-phosphonomethyl-hydroxytryptamine); N,N-bis(phosphonomethyl)-taurine;N,N-bis(phosphonomethyl)-tryptamine; N,N-bis(phosphonomethyl)-tyramineand N,N′-bis(phosphonomethyl)-ornithine.
 15. The composition of claim10, wherein the N-(phosphonoalkyl)-amino acid, related compound orderivative thereof has the following formula:R₁CH(NR₂R₃)(CH₂)_(m)COR₄ wherein R₁ is H, an alkyl group having 1 to 19carbon atoms, an aryl group having 6 to 19 carbon atoms or an aralkylgroup having 7 to 19 carbon atoms; and R₁ can also carry —OH, —SH,—SCH₃, —NH₂, —NR₂R₃, —COR₄, —NHCONH₂, —NHC(═NR₂)NH₂, imidazole,pyrrolidine or other heterocyclic group; m is an integer from 0 to 5; R₂is a phosphonoalkyl group having a formula (HO)₂PO(CH₂)_(n)—; R₃ is H ora phosphonoalkyl group having a formula (HO)₂PO(CH₂)_(n)—; n is aninteger from 1 to 9; R₄ is —NH₂ or —OR₅, R₅ is H, an alkyl group having1 to 19 carbon atoms, an aryl group having 6 to 19 carbon atoms or anaralkyl group having 7 to 19 carbon atoms; and the H attached to anycarbon atom can be substituted by I, F, Cl, Br, OH or an alkoxy grouphaving 1 to 9 carbon atoms; and wherein the N-(phosphonoalkyl)-aminoacid, related compound or derivative thereof is in a form as a freeacid, salt, partial salt, lactone, amide or ester, or in stereoisomericor non-stereoisomeric form.
 16. The composition of claim 10, wherein thephosphonoalkyl of the N-(phosphonoalkyl)-amino acid compound, relatedcompound or compound derived therefrom is selected from the groupconsisting of phosphonomethyl, phosphonoethyl, phosphonopropyl,phosphonoisopropyl, phosphonobutyl, phosphonoisobutyl, phosphonopentyl,phosphonoisopentyl, phosphonooctyl and phosphonoisooctyl.
 17. Thecomposition of claim 10, wherein the compound is anN-(phosphonoalkyl)-amino acid.
 18. The composition of claim 10, whereinthe compound is an N-(phosphonomethyl)-amino acid.
 19. The compositionof claim 18, wherein the N-(phosphonomethyl)-amino acid in a form as afree acid, salt, partial salt, lactone, amide or ester, or in astereoisomeric or non-stereoisomeric form, is selected from the groupconsisting of N-(phosphonomethyl)-alanine, N-(phosphonomethyl)-arginine,N-(phosphonomethyl)-asparagine, N-(phosphonomethyl)-aspartic acid,N-(phosphonomethyl)-cysteine, N-(phosphonomethyl)-glutamic acid,N-(phosphonomethyl)-glutamine, N-(phosphonomethyl)-glycine,N-(phosphonomethyl)-histidine, N-(phosphonomethyl)-isoleucine,N-(phosphonomethyl)-leucine, N-(phosphonomethyl)-lysine,N-(phosphonomethyl)-methionine, N-(phosphonomethyl)-phenylalanine,N-(phosphonomethyl)-proline, N-(phosphonomethyl)-serine,N-(phosphonomethyl)-threonine, N-(phosphonomethyl)-tryptophan,N-(phosphonomethyl)-tyrosine and N-(phosphonomethyl)-valine.
 20. Thecomposition of claim 10, wherein the N-(phosphonoalkyl)-amino acidcompound, related compound or compound derived therefrom in a form as afree acid, salt, partial salt, lactone, amide or ester, or instereoisomeric or non-stereoisomeric form, is selected from the groupconsisting of N-(phosphonomethyl)-β-alanine,N-(phosphonomethyl)-γ-aminobutanoic acid,N-(phosphonomethyl)-β-aminoisobutanoic acid,N-(phosphonomethyl)-anserine, N-(phosphonomethyl)-aminolevulinic acid,N-(phosphonomethyl)-carnosine, N-(phosphonomethyl)-canaline,N-(phosphonomethyl)-canavanine, N-(phosphonomethyl)-citrulline,N-(phosphonomethyl)-creatine, N-(phosphonomethyl)-creatinine,N-(phosphonomethyl)-cysteine sulfinic acid, N-(phosphonomethyl)-cystine,N-(phosphonomethyl)-cycloserine,N-(phosphonomethyl)-dopa[N-(phosphonomethyl)-3,4-dihydroxyphenylalanine],N-(phosphonomethyl)-dopamine(hydroxytyramine),N-(phosphonomethyl)-ethionine, N-(phosphonomethyl)-glutathione,N-(phosphonomethyl)-guanidinoacetic acid,N-(phosphonomethyl)-3-guanidinopropanoic acid,N-(phosphonomethyl)-4-guanidinobutanoic acid,N-(phosphonomethyl)-homocarnosine, N-(phosphonomethyl)-homocysteine,N-(phosphonomethyl)-homoserine,N-(phosphonomethyl)-4-hydroxyphenylglycine,N-(phosphonomethyl)-hydroxyglutamic acid,N-(phosphonomethyl)-hydroxylysine, N-(phosphonomethyl)-hydroxyproline,N-(phosphonomethyl)-hypusine, N-(phosphonomethyl)-homoarginine,N-(phosphonomethyl)-homocitrulline, N-(phosphonomethyl)-homocystine,N-(phosphonomethyl)-homophenylalanine,N-(phosphonomethyl)-homotryptophan, N-(phosphonomethyl)-hydroxylysine,N-(phosphonomethyl)-hydroxyarginine,N-(phosphonomethyl)-hydroxyhomoarginine,N-(phosphonomethyl)-hydroxycitrulline,N-(phosphonomethyl)-hydroxyomithine, N-(phosphonomethyl)-hydroxyvaline,N-(phosphonomethyl)-indospicine, N-(phosphonomethyl)-methoxinine,N-(phosphonomethyl)-methylarginine, N-(phosphonomethyl)-methylhistidine,N-(phosphonomethyl)-methyllysine, N-(phosphonomethyl)-methylornithine,N-(phosphonomethyl)-methylserine, N-(phosphonomethyl)-norvaline,N-(phosphonomethyl)-ornithine, N-(phosphonomethyl)-oxalysine,N-(phosphonomethyl)-penicillamine(N-phosphonomethyl-dimethylcysteine),N-(phosphonomethyl)-phenylglycine, N-(phosphonomethyl)-3-phenylserine,N-(phosphonomethyl)-sarcosine (N-phosphonomethyl-N-methyl-glycine),N-(phosphonomethyl)-serotonin (N-phosphonomethyl-hydroxytryptamine),N-(phosphonomethyl)-taurine, N-(phosphonomethyl)-tryptamine andN-(phosphonomethyl)-tyramine.
 21. The composition of claim 10, whereinthe N-(phosphonoalkyl)-amino acid compound, related compound or compoundderived therefrom in a form as a free acid, salt, partial salt, lactone,amide or ester, or in stereoisomeric or non-stereoisomeric form, isselected from the group consisting of N-(phosphonomethyl)-asparagine,N-(phosphonomethyl)-asparaginamide, N-(phosphonomethyl)-γ-aminobutanoicacid, N-(phosphonomethyl)-arginine, N-(phosphonomethyl)-argininamide,N-(phosphonomethyl)-arginine ethyl ester, N-(phosphonomethyl)-creatine,N-(phosphonomethyl)-creatinine, N-(phosphonomethyl)-cysteine,N-(phosphonomethyl)-glutamic acid, N-(phosphonomethyl)-glutamic aciddiethyl ester, N-(phosphonomethyl)-glutamine,N-(phosphonomethyl)-glutaminamide, N-(phosphonomethyl)-glutamine ethylester, N-(phosphonomethyl)-glutathione, N-(phosphonomethyl)-glycine,N-(phosphonomethyl)-glycinamide, N-(phosphonomethyl)-glycine ethylester, N-(phosphonomethyl)-glycine propyl ester,N-(phosphonomethyl)-glycine isopropyl ester,N-(phosphonomethyl)-4-hydroxyphenylglycine, N-(phosphonomethyl)-lysine,N-(phosphonomethyl)-lysinamide, N-(phosphonomethyl)-lysine ethyl ester,N-(phosphonomethyl)-ornithine, N-(phosphonomethyl)-proline,N-(phosphonomethyl)-prolinamide, N-(phosphonomethyl)-proline ethylester, N-(phosphonomethyl)-proline propyl ester,N-(phosphonomethyl)-proline isopropyl ester, N-(phosphonomethyl)-serine,N-(phosphonomethyl)-tyrosine and N-(phosphonomethyl)-tyramine.
 22. Thecomposition of claim 10, wherein the composition further comprises acosmetic, pharmaceutical or other topically active agent.
 23. Thecomposition of claim 22, wherein the cosmetic, pharmaceutical or othertopically active agent is selected from the group consisting ofhydroxyacids, ketoacids and related compounds; phenyl alphaacyloxyalkanoic acids and derivatives; N-acyl-aldosamines, N-acylaminoacids and related N-acyl compounds; local analgesics and anesthetics;anti-acne agents; anti-bacterial agents; anti-yeast agents; anti-fungalagents; anti-viral agents; anti-infective agents; anti-dandruff agents;anti-dermatitis agents; anti-eczema agents; anti-histamine agents;anti-pruritic agents; anti-emetics; anti-motion sickness agents;anti-inflammatory agents; anti-hyperkeratotic agents; antiperspirants;anti-psoriatic agents; anti-rosacea agents; anti-seborrheic agents; hairconditioners and hair treatment agents; anti-aging and anti-wrinkleagents; anti-anxiety agents; anti-convulsant agents; anti-depressantagents; sunblock and sunscreen agents; skin lightening agents;depigmenting agents; astringents; cleansing agents; corn, callus or wartremoving agents; skin plumping agents; skin volumizing agents; skinfirming agents; matrix metalloproteinase (MMP) inhibitors; topicalcardiovascular agents; wound-healing agents; gum disease or oral careagents; amino acids; peptides; dipeptides; tripeptides; glutathione andits derivatives; oligopeptides; polypeptides; carbohydrates;aminocarbohydrates; vitamins; corticosteroids; tanning agents; hormonesand retinoids.
 24. The composition of claim 22, wherein the cosmetic,pharmaceutical or other topically active agent as stated or as freebase, free acid, ester, amide, lactone or salt form is selected from thegroup consisting of: abacavir, abciximab, acamprosate, acarbose,acebutolol, acetaminophen, acetaminosalol, acetazolamide, acetic acid,acetohydroxamic acid, N-acetylcysteine and its esters,N-acetylglutathione and its esters, acitretin, aclometasonedipropionate, acrivastine, acthrel, actidose, actigall, acyclovir,adalimumab, adapalene, adefovir dipivoxil, adenosine, agalsidase,albendazole, albumin, albuterol, aldesleukin, alefacept, alemtuzumab,alendronate, alfuzosin, alitretinoin, allantoin, allium, allopurinol,alloxanthine, almotriptan, alosetron, alpha tocopheral,alpha,-proteinase, alprazolam, alprenolol, alprostadil, alteplase,altretamine, aluminum acetate, aluminum chloride, aluminumchlorohydroxide, aluminum hydroxide, amantadine, amifostine, amiloride,aminacrine, amino acid, aminobenzoate, p-aminobenzoic acid, aminocaproicacid, aminohippurate, aminolevulinic acid, aminosalicylic acid,amiodarone, amitriptyline, amlodipine, amocarzine, amodiaquin,amorolfine, amoxapine, amoxicillin, amphetamine, amphotericin,ampicillin, amprenavir, anagrelide, anakinra, anastrozole, anisindione,anthralin, antihemophilic, antithrombin, anti-thymocyte, antivenin,apomorphine, aprepitant, aprotinin, arbutin, argatroban, aripiprazole,arnica, ascorbic acid and its esters, ascorbyl palmitate, aspirin,atazanavir, atenolol, atomoxetine, atorvastatin, atovaquone, atropine,azathioprine, azelaic acid, azelastine, azithromycin, baclofen,bacitracin, balsalazide, balsam, basiliximab, beclomethasonedipropionate, bemegride, benazepril, bendroflumethiazide, benzocaine,benzonatate, benzophenone, benzoyl peroxide, benztropine, bepridil, betacarotene, betamethasone dipropionate, betamethasone valerate, betaxolol,bethanechol, bevacizumab, bexarotene, bicalutamide, bimatoprost,bioflavonoids, biotin, biperiden, bisacodyl, bisoprolol, bivalirudin,bortezomib, bosentan, botulinum, brimonidine, brinzolamide,bromocriptine, brompheniramine, budesonide, bumetanide, bupivacaine,buprenorphine, bupropion, burimamide, buspirone, busulfan, butabarbital,butalbital, butenafine, butoconazole, butorphanol, butyl aminobenzoate,cabergoline, caffeic acid, caffeine, calcipotriene, calcitonin-salmon,calcitriol, calfactant, camellia sinensis, camphor, candesartancilexetil, capecitabine, capreomycin, capsaicin, captopril,carbamazepine, carbamide peroxide, carbidopa, carbinoxamine, cefditorenpivoxil, cefepime, cefpodoxime proxetil, celecoxib, cetirizine,cevimeline, chitosan, chlordiazepoxide, chlorhexidine, chloroquine,chlorothiazide, chloroxylenol, chlorpheniramine, chlorpromazine,chlorpropamide, ciclopirox, cilostazol, cimetidine, cinacalcet,ciprofloxacin, citalopram, citric acid, cladribine, clarithromycin,clemastine, clindamycin, clioquinol, clobetasol propionate, clocortolonepivalate, clomiphene, clonidine, clopidogrel, clotrimazole, clozapine,coal tar, coal tar extracts (LCD), codeine, cromolyn, crotamiton,cyclizine, cyclobenzaprine, cycloserine, cytarabine, dacarbazine,dalfopristin, dapsone, daptomycin, daunorubicin, deferoxamine,dehydroepiandrosterone, delavirdine, desipramine, desloratadine,desmopressin, desoximetasone, dexamethasone, dexmedetomidine,dexmethylphenidate, dexrazoxane, dextroamphetamine, diazepam,diclofenac, dicyclomine, didanosine, dihydrocodeine, dihydromorphine,diltiazem, 6,8-dimercaptooctanoic acid (dihydrolipoic acid),diphenhydramine, diphenoxylate, dipyridamole, disopyramide, dobutamine,dofetilide, dolasetron, donepezil, dopa esters, dopamide, dopamine,dorzolamide, doxepin, doxorubicin, doxycycline, doxylamine, doxepin,duloxetine, dyclonine, econazole, efalizumab, eflomithine, eletriptan,emtricitabine, enalapril, ephedrine, epinephrine, epinine, epirubicin,eptifibatide, ergotamine, erythromycin, escitalopram, esmolol,esomeprazole, estazolam, estradiol, etanercept, ethacrynic acid, ethinylestradiol, etidocaine, etomidate, famciclovir, famotidine, felodipine,fentanyl, ferulic acid, fexofenadine, flecamide, fluconazole,flucytosine, fluocinolone acetonide, fluocinonide, 5-fluorouracil,fluoxetine, fluphenazine, flurazepam, fluticasone propionate,fluvoxamine, formoterol, furosemide, galactarolactone, galactonic acid,galactonolactone, galantamine, gatifloxacin, gefitinib, gemcitabine,gemifloxacin, glucarolactone, gluconic acid, gluconolactone, glucuronicacid, glucuronolactone, glycolic acid, griseofulvin, guaifenesin,guanethidine, N-guanylhistamine, haloperidol, haloprogin,hexylresorcinol, homatropine, homosalate, hydralazine,hydrochlorothiazide, hydrocortisone, hydrocortisone 21-acetate,hydrocortisone 17-butyrate, hydrocortisone 17-valerate, hydrogenperoxide, hydromorphone, hydroquinone, hydroquinone monoether,hydroxyzine, hyoscyamine, hypoxanthine, ibuprofen, ichthammol,idarubicin, imatinib, imipramine, imiquimod, indinavir, indomethacin,infliximab, irbesartan, irinotecan, isoetharine, isoproterenol,itraconazole, kanamycin, ketamine, ketanserin, ketoconazole, ketoprofen,ketotifen, kojic acid, labetalol, lactic acid, lactobionic acid,lamivudine, lamotrigine, lansoprazole, letrozole, leuprolide,levalbuterol, levofloxacin, lidocaine, linezolid, lobeline, loratadine,loperamide, losartan, loxapine, lysergic diethylamide, mafenide, malicacid, maltobionic acid, mandelic acid, maprotiline, mebendazole,mecamylamine, meclizine, meclocycline, memantine, menthol, meperidine,mepivacaine, mequinol, mercaptopurine, mescaline, metanephrine,metaproterenol, metaraminol, metformin, methadone, methamphetamine,methotrexate, methoxamine, methyldopa esters, methyldopamide,3,4-methylenedioxymethamphetamine, methyllactic acid, methyl nicotinate,methylphenidate, methyl salicylate, metiamide, metolazone, metoprolol,metronidazole, mexiletine, miconazole, midazolam, midodrine, miglustat,minocycline, minoxidil, mirtazapine, mitoxantrone, moexiprilat,molindone, monobenzone, morphine, moxifloxacin, moxonidine, mupirocin,nadolol, naftifine, nalbuphine, nalmefene, naloxone, naproxen,nefazodone, nelfinavir, neomycin, nevirapine, nicardipine, nicotine,nifedipine, nimodipine, nisoldipine, nitrofurantoin, nizatidine,norepinephrine, nystatin, octopamine, octreotide, octylmethoxycinnamate, octyl salicylate, ofloxacin, olanzapine, olmesartanmedoxomil, olopatadine, omeprazole, ondansetron, oxiconazole,oxotremorine, oxybenzone, oxybutynin, oxycodone, oxymetazoline, padimateO, palonosetron, pantothenic acid, pantoyl lactone, paroxetine,pemoline, penciclovir, penicillamine, penicillins, pentazocine,pentobarbital, pentostatin, pentoxifylline, pergolide, perindopril,permethrin, phencyclidine, phenelzine, pheniramine, phenmetrazine,phenobarbital, phenol, phenoxybenzamine, phentolamine, phenylephrine,phenylpropanolamine, phenyloin, physostigmine, pilocarpine,pimecrolimus, pimozide, pindolol, pioglitazone, pipamazine, piperonylbutoxide, pirenzepine, podofilox, povidone iodine, pramipexole,pramoxine, prazosin, prednisone, prenalterol, prilocalne, procainamide,procaine, procarbazine, promazine, promethazine, promethazinepropionate, propafenone, propoxyphene, propranolol, propylthiouracil,protriptyline, pseudoephedrine, pyrethrin, pyrilamine, pyrimethamine,quetiapine, quinapril, quinethazone, quinidine, quinupristin,rabeprazole, reserpine, resorcinol, retinal, 13-cis retinoic acid,retinoic acid, retinol, retinyl acetate, retinyl palmitate, ribavirin,ribonic acid, ribonolactone, rifampin, rifapentine, rifaximin, riluzole,rimantadine, risedronic acid, risperidone, ritodrine, rivastigmine,rizatriptan, ropinirole, ropivacaine, salicylamide, salicylic acid,salmeterol, scopolamine, selegiline, selenium sulfide, serotonin,sertaconazole, sertindole, sertraline, shale tar, sibutramine,sildenafil, sotalol, streptomycin, strychnine, sulconazole,sulfacetamide, sulfabenz, sulfabenzamide, sulfabromomethazine,sulfacetamide (sodium sulfacetamide), sulfachlorpyridazine, sulfacytine,sulfadiazine, sulfadimethoxine, sulfadoxine, sulfaguanole, sulfalene,sulfamethizole, sulfamethoxazole, sulfanilamide, sulfapyrazine,sulfapyridine, sulfasalazine, sulfasomizole, sulfathiazole,sulfisoxazole, sulfur, tacrolimus, tadalafil, tamsulosin, tartaric acid,tazarotene, tegaserod, telithromycin, telmisartan, temozolomide,tenofovir disoproxil, terazosin, terbinafine, terbutaline, terconazole,terfenadine, tetracaine, tetracycline, tetrahydrozoline, thalidomide,theobromine, theophylline, thiabendazole, thioctic acid (lipoic acid),thioridazine, thiothixene, thymol, tiagabine, timolol, timidazole,tioconazole, tirofiban, tizanidine, tobramycin, tocamide, tolazoline,tolbutamide, tolnaftate, tolterodine, tramadol, tranylcypromine,trazodone, triameinolone acetonide, triamcinolone diacetate,triamcinolone hexacetonide, triamterene, triazolam, triclosan,triflupromazine, trimethoprim, trimipramine, tripelennamine,triprolidine, tromethamine, tropic acid, tyramine, undecylenic acid,urea, urocanic acid, ursodiol, valacyclovir, vardenafil, venlafaxine,verapamil, vitamin E acetate, voriconazole, warfarin, wood tar,xanthine, zafirlukast, zaleplon, zinc pyrithione, ziprasidone,zolmitriptan and zolpidem.